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CN115304502B - FOXM1 inhibitor and preparation method and application thereof - Google Patents

FOXM1 inhibitor and preparation method and application thereof Download PDF

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Publication number
CN115304502B
CN115304502B CN202210929820.3A CN202210929820A CN115304502B CN 115304502 B CN115304502 B CN 115304502B CN 202210929820 A CN202210929820 A CN 202210929820A CN 115304502 B CN115304502 B CN 115304502B
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compound
nmr
dmso
preparation
yield
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CN115304502A (en
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薛司徒
高岩
李卓荣
谢卓松
周子颖
杨鹤显
易红
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Institute of Medicinal Biotechnology of CAMS
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    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a FOXM1 inhibitor comprising a compound of formula I, a pharmaceutical salt or ester thereof, a solvate, an isomer, a polymorphic form, an isotope labeled compound, a metabolite or prodrug, and simultaneously providing a combination, preparation method and application thereof. Through extensive research and screening, it has been found that the above series of compounds can exert anti-tumor activity by inhibiting FOXM1 and downregulating the level of its downstream target protein. Therefore, this series of compounds can be used for the prevention and/or treatment of tumor diseases.

Description

FOXM1 inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, in particular to a FOXM1 inhibitor and a preparation method thereof, and also relates to application of the inhibitor in exerting anti-tumor effect, a pharmaceutical composition taking the compound as an active component and application of the composition.
Background
Fork box (Fox) transcription factors, which are widely available from yeast to human, belong to a subgroup of "winged helix" class proteins, which have more than 50 members involved in regulating physiological processes such as cell differentiation, proliferation, metabolism and apoptosis, respectively. FOXM1 (forkhead box protein M1), a member of this family of transcription factors, is the primary regulator of the cell cycle, and there is increasing evidence that FOXM1 is also involved in the regulation of many other cellular processes by activating specific transcription pathways.
FOXM1 is also known as tricent (mouse), HFH-11 (human), WIN or INS-1 (rat), MPP-2 (partially human cDNA) or FKH L-5. The human FOXM1 gene maps to the 12p13 chromosome band, with a full length of about 25kb, consisting of 10 exons, of which 2 exons A1 and A2 are selective ligation sites. FOXM1 plays a major role in regulating transcriptional activation of cytokines involved in cell cycle transition, whose transcriptional activity is cell cycle dependent. The transcriptional activity control mechanism of FOXM1 is to control its phosphorylation state at a specific cell cycle to affect the inter-domain interactions of the protein itself. In normally proliferating cells, FOXM1 is able to promote proliferation of cells, playing an important role in the G1/S phase and G2/M phase transition processes. FOXM1 has been reported to promote cell entry into S-phase and M-phase by activating Cyclin a/CDK2, cyclin B1, cyclin a, aurora B kinase, plk1, cdc25B, p, and p27, etc. FOXM1 also plays a key role in chromosome segregation and spindle assembly by regulating the expression of proteins such as CENPA, CENPB and CENPF.
As a transcription factor for stimulating proliferation, plays an important role in the development and progression of tumors, and participates in proliferation, invasion, metastasis, angiogenesis, stem cell generation and the like of tumor cells. Especially, in recent years, FOXM1 is found to be closely related to the drug resistance of a chemotherapeutic drug, for example, over-expression of FOXM1 in sensitive cells can induce the FOXM to resist the drug, and silencing FOXM1 can remarkably reduce the proliferation rate of the drug resistant cells and improve the drug sensitivity, so that the targeted FOXM1 can sensitize tumor cells to the chemotherapeutic drug.
The key point of exploring the key amino acid site of FOXM1 protein, the effect on downstream pathway after binding small molecule and tumor therapeutic effect is to find the chemical molecule specifically binding to FOXM1 protein. The active compounds related to FOXM1 reported in the literature are mainly divided into two types, one is a compound which can down-regulate the expression level of FOXM1 and inhibit tumor proliferation, and the other is a compound which binds to FOXM1 and inhibits its activity.
In recent years, the research shows that thiazole antibiotics such as the salt house mycin A and the thiostrepton can inhibit the expression of the FOXM1, and have the effects of inhibiting the proliferation of tumor cells and inducing the apoptosis of the tumor cells. However, due to the proteasome inhibition properties of thiazole antibiotics, these drugs are likely to affect various signal pathways in addition to FOXM1, have a strong off-target effect, and are not suitable for elucidating the biological effects of FOXM1 after binding to DNA. The novel peptide small molecule 9R-P201 can also obviously reduce the expression level of FOXM1 in HepG2 cells, inhibit cell proliferation, angiogenesis and induce apoptosis. Recently, researchers have found that paeoniflorin, a natural product, can also inhibit the expression of FOXM1, can inhibit cell growth in colon cancer cells, induce apoptosis and inhibit cell invasion and metastasis. In addition, the natural products sophoridine and plumbagin also inhibit the proliferation of human medulloblastoma and glioma cells by inhibiting the expression of FOXM1 in the cells, respectively.
In 2014 Gormally, the small-molecule FDI6 can inhibit the activity of FOXM1 through high-throughput screening, and can prevent the normal activation of a target gene downstream of the FOXM1 and induce apoptosis of laryngeal cancer Hep-2 cells by blocking the binding of the small-molecule FDI6 with DNA (IC50=22.5 mu M), so that the discovery of the compound can promote the progress of the FOXM1 as a tumor treatment target, and the discovery of the compound can promote the progress of the FOXM1 as a tool molecule for researching the FOXM1 by replacing thiostrepton in recent years. Recently, scholars have discovered that the hypoglycemic agent troglitazone (ic50=122.4 μm) capable of binding to FOXM1 protein by establishing a molecular docking method, and optimized by a chemical method, obtained a derivative capable of dissociating FOXM1-DNA complex, and capable of inhibiting tumor cell colony formation. Sun et al also determined a novel small molecular compound RCM-1 through high throughput screening, which can inhibit the activity of FOXM1 in vitro, but the research focus is on the effects of preventing goblet cell metaplasia, reducing lung inflammation and the like, and the application in tumor treatment has not been developed. Honokiol is a natural product with wide antitumor activity, and recently Halasi and other researches have found that honokiol inhibits FOXM1 activity by binding to FOXM1, thereby explaining its biological activity in cancer cells.
At present, less active compounds or inhibitors related to FOXM1 are found, and thiazole antibiotics, novel peptides 9R-P201, FDI6, troglitazone, RCM-1, natural products paeoniflorin, sophoridine, plumbagin, magnolol and the like are all in an early research stage, and the FOXM1 inhibitor does not enter a clinical medicine research stage. For the above reasons, the system has developed an inhibitor study of FOXM1 and found that a compound capable of specifically binding to FOXM1 is necessary.
Disclosure of Invention
It is an object of the present invention to provide a group of FOXM1 inhibitor compounds, pharmaceutically acceptable salts or esters, solvates, isomers, polymorphs, isotopically-labeled compounds, metabolites or prodrugs thereof.
It is a further object of the present invention to provide the use of said compound, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically-labeled compound, metabolite or prodrug thereof in the manufacture of a medicament for inhibiting FOXM1, an anti-tumor or related disorder.
It is a further object of the present invention to provide a pharmaceutical composition or pharmaceutical formulation of said compound, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically-labelled compound, metabolite or prodrug thereof as active ingredient, and the use of the pharmaceutical composition in the treatment or prophylaxis of tumour associated diseases.
Definition of terms
The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The nomenclature used herein and the laboratory procedures in organic chemistry, pharmaceutical chemistry, biology described herein are those well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used in the description of embodiments of the invention and the appended claims, the singular forms "a," "an," "the," and "the" are used to refer to the singular and the plural of the article unless the context clearly dictates otherwise. For example, a compound includes one or more than one compound.
As used herein, "and/or" refers to and includes any and all possible combinations of one or more of the associated listed items.
As used herein, the term "disease" or "patient" refers to any change in a physical state or some organ that interrupts or interferes with the performance of its function and/or causes symptoms.
As used herein, the term "tumor" refers to a localized tumor formed by abnormal proliferation of cells of the body under the influence of various pathogenic factors, including benign tumors, malignant tumors, and borderline tumors. Including but not limited to breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
As used herein, the term "treatment" is intended to reduce or eliminate the disease state or condition for which it is intended. A subject is successfully "treated" if the subject has received a therapeutic amount of a compound, or a pharmaceutically acceptable salt, isomer, polymorph, solvate, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition thereof, according to the methods described herein, and the subject exhibits an observable and/or detectable decrease or improvement in one or more indications and symptoms. It is also to be understood that the treatment of the disease state or condition described includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result.
As used herein, the term "subject" may refer to a patient or other animal receiving a composition of the invention to treat, prevent, ameliorate and/or alleviate a disease or condition described herein, particularly humans and mammals.
Subject 1
FOXM1 inhibitors comprising a compound of formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically labeled compound, metabolite or prodrug thereof:
Wherein X is selected from the group consisting of ：―(CH2)n―、―(CH2)mO(CH2)n-m―、―(CH2)kCH(R)(CH2)n-k―;
R a can be one or two or more, independently selected from H, halogen, NO 2, CN, OH, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, phenoxy, benzyloxy, - (-CH 2)hC(O)Rx、―NRyRz;
R x is selected from H, OH, NH 2, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy;
r y、Rz can be independently selected from H, C-C6 linear or branched alkyl, C2-C6 linear or branched alkenyl;
Q represents O, NH or NR 5;
R 5 is selected from C1-C6 straight or branched alkyl;
R 4 is selected from H, - (CH 2)mO(CH2)n-m OH, R substituted or unsubstituted C1-C7 straight or branched alkyl, R substituted or unsubstituted C3-C7 straight or branched cycloalkyl, R substituted or unsubstituted 3-6 membered saturated or unsaturated heteroalkyl containing 1 or 2 members selected from O, S or N, R substituted or unsubstituted aryl, R substituted or unsubstituted 5-or 6 membered heteroaryl, aldehyde, C2-C5 carbonyl, C1-C5 carboxyl, C1-C5 carboxylate;
The R substituents may be one or two or more, independently selected from: halogen, OH, C1-C6 hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C5 carboxyl, C2-C5 carbonyl, C1-C5 carboxylate, C1-C5 amido, NH 2;
n is selected from 1,2,3,4, 5,6, 7 or 8; m is selected from 1,2,3,4, 5,6, 7 or 8; k is selected from 0, 1,2,3,4, 5,6, 7 or 8; h is selected from 0, 1,2 or 3.
In some cases, X is selected from (CH 2)n), e.g., ：―(CH2)2―、―(CH2)3―、―(CH2)4―、―(CH2)5― or (CH 2)6).
In some cases, X is selected from (CH 2)mO(CH2)n-m, for example:
―CH2OCH2―、―CH2O(CH2)2―、―CH2O(CH2)3―、―CH2O(CH2)4―、―CH2O(CH2)5―、―( CH2)2O―、―(CH2)2OCH2―、―(CH2)2O(CH2)2―、―(CH2)2O(CH2)3―、―(CH2)2O(CH2)4―、―(CH2)3O―、―(CH2)3OCH2―、―(CH2)3O(CH2)2―、―(CH2)3O(CH2)3―、―(CH2)4O―、―(CH2)4OCH2―、―(CH2)4O(CH2)2―、―(CH2)5O― Or (CH 2)5OCH2).
In some cases, X is selected from (CH 2)kCH(R)(CH2)n-k, for example:
―CH(R)CH2―、―CH(R)(CH2)2―、―CH(R)(CH2)3―、―CH(R)(CH2)4―、―CH(R)(CH2)5―、―CH2CH(R)CH2―、―CH2CH(R)(CH2)2―、―CH2CH(R)(CH2)3―、―CH2CH(R)(CH2)4―、―CH2C H(R)(CH2)5―、―(CH2)2CH(R)―、―(CH2)2CH(R)CH2―、―(CH2)2CH(R)(CH2)2―、―(CH2)2CH(R)( CH2)3―、―(CH2)2CH(R)(CH2)4―、―(CH2)3CH(R)―、―(CH2)3CH(R)CH2―、―(CH2)3CH(R)(CH2)2―、―(CH2)3CH(R)(CH2)3―、―(CH2)4CH(R)―、―(CH2)4CH(R)(CH2)2―、―(CH2)5CH (R)― Or (CH 2)5CH(R)CH2).
In some cases, R a may be one, two, three, or four, and when R a is plural, it may be the same or different.
In some cases, R a is selected from H, halogen, NO 2, CN, phenoxy, or benzyloxy.
In some cases, R a is selected from C1-C6 straight or branched alkyl groups, for example:
―CH3、―CH2CH3、―CH2CH2CH3、―CH(CH3)CH3-、―C(CH3)3-、―CH2CH2CH2CH3-、―CH (CH3)CH2CH3、―CH(CH3)CH2(CH3)、―CH(CH2CH3)CH3、―C(CH3)2CH3、―CH2CH2CH2CH2CH3 or-CH 2CH2CH2CH2CH2CH3.
In some cases, R a is selected from C1-C6 straight or branched alkoxy groups, for example:
―OCH3、―OCH2CH3、―OCH2CH2CH3、―OCH(CH3)CH3-、―OC(CH3)3-、―OCH2CH2CH2C H3-、―OCH(CH3)CH2CH3、―OCH(CH3)CH2(CH3)、―OCH(CH2CH3)CH3、―OC(CH3)2CH3、―OC H2CH2CH2CH2CH3 or-OCH 2CH2CH2CH2CH2CH3.
In some cases, R a is selected from C1-C6 straight or branched alkoxy groups, for example:
―C(O)H、―C(O)OH、―C(O)NH2、―C(O)CH3、―C(O)CH2CH3、―C(O)C3H7、―C(O)C4H9、―C(O)C5H11、―C(O)OCH3、―C(O)OC2H5、―C(O)OC3H7、―C(O)OC4H9、―C(O)OC5H11、―C H2C(O)H、―CH2C(O)OH、―CH2C(O)NH2、―CH2C(O)CH3、―CH2C(O)C2H5、―CH2C(O)C3H7、―CH2C(O)C4H9、―CH2C(O)C5H11、―CH2C(O)OCH3、―CH2C(O)OC2H5、―CH2C(O)OC3H7、―C H2C(O)OC4H9 or-CH 2C(O)OC5H11.
In some cases, R a is selected from the group consisting of-NR yRz, for example:
―NH2、―NHCH3、―NHC2H5、―NHC3H7、―NHC4H9、―N(CH3)2、―NH(CH3)C2H5、―NH( CH3)C3H7、―NH(CH3)C4H9、―N(C2H5)2、―NH(C2H5)C3H7、―NH(C2H5)C4H9、―N(C3H7)2、―NH (C3H7)C4H9 or-N (C 4H9)2).
In some cases, R 4 is selected from the group consisting of (CH 2)mO(CH2)n-m OH, for example:
―CH2OCH2OH、―CH2O(CH2)2OH、―CH2O(CH2)3OH、―CH2O(CH2)4OH、―CH2O(CH2)5OH 、―(CH2)2OCH2OH、―(CH2)2O(CH2)2OH、―(CH2)2O(CH2)3OH、―(CH2)2O(CH2)4OH、―(CH2)3OC H2OH、―(CH2)3O(CH2)2OH、―(CH2)3O(CH2)3OH、―(CH2)4O(CH2)2OH Or (CH 2)5OCH2 OH).
In some cases, R 4 is selected from:
H、―(CH2)2O(CH2)2OH、―C(O)OH、―CH2C(O)OH、―C(O)OCH3、―CH2C(O)CH3、―C(O)C2H5、 Methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, which may be substituted by one or more R.
In some cases, R 4 is selected from the group consisting of 1 or 2 selected from: o, S or 3-6 membered saturated or unsaturated heteroalkyl groups of N, for example: saturated or unsaturated oxiranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl tetrahydropyranyl or pyranyl groups, which may be substituted with one or more R.
In some cases, R 4 is selected from the group consisting of 5-or 6-membered heteroaryl groups, such as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which may be substituted with one or more R.
In some cases, R 4 is selected from aldehyde groups, for example:
―C(O)H、―CH2C(O)H、―(CH2)2C(O)H、―(CH2)3C(O)H、―(CH2)4C(O)H.
In some cases, R 4 is selected from C2-C5 carbonyl is selected from ：―C(O)CH3、―C(O)C2H5、―C(O)C3H7、―C(O)C4H9、 CH2C(O)CH3、―CH2C(O)C2H5、―CH2C(O)C3H7、―(CH2)2C(O)CH3、―(CH2)2C(O)C2H5 or (CH 2)3C(O)CH3;
In some cases, R 4 is selected from C1-C5 carboxyl groups, e.g ：―C(O)OH、―CH2C(O)OH、―(CH2)2C(O) OH、―(CH2)3C(O)OH、―(CH2)4C(O)OH.
In some cases, R 4 is selected from C1-C5 carboxylate groups, for example:
―C(O)OCH3、―C(O)OC2H5、―C(O)OC3H7、―C(O)OC4H9、―CH2C(O)OCH3、―CH2C(O)OC2H5、―CH2C(O)OC3H7、―C2H4C(O)OCH3、―C2H4C(O)OC2H5、―C3H6C(O)O CH3.
In some cases, R 4 is selected from C1-C5 amide groups, for example:
―C(O)NH2、―CH2C(O)NH2、―(CH2)2C(O)NH2、―(CH2)3C(O)NH2、―(CH2)4C(O)NH2.
R in the present application and typical embodiments may be selected from F, br, cl, OH, C-C6 hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C5 carboxyl, C2-C5 carbonyl, C1-C5 carboxylate, C1-C5 amide, NH 2, each substituent being as described above, and when there are a plurality of R groups, the R groups may be the same or different.
As some particularly preferred cases, X is selected from the following groups:
―(CH2)2O―、―(CH2)2OCH2―、―(CH2)2O(CH2)2―、―(CH2)6― or-CH 2CH(OH)CH2 -;
R a may be one or two or three, which are independently selected from H, F, br, cl, NO 2, CN, OH, methyl, methoxy, phenoxy, benzyloxy 、―C(O)H、―C(O)OH、―C(O)NH2、―C(O)CH3、―C(O)OCH3、―C(O)OC2H5、―NH2、―NHCH3 or-N (CH 3)2;
q represents O, NH or NCH 3;
R 4 is selected from ：H、―(CH2)2O(CH2)2OH、―C(O)OH、―CH2C(O)OH、―C(O)OCH3、―CH2C(O)CH3、―C(O)C2H5、 methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxirane, phenyl, tetrahydrofuranyl, tetrahydropyran, piperidinyl, morpholinyl, piperazinyl, pyranyl, piperidinyl, pyrrolidinylamino, furanyl, thiazolyl, thienyl, pyrrolyl, pyrimidinyl, pyridinyl, or uracil yl;
the R substituents may be one or two, which are independently selected from: F. br, cl, OH, methyl, methoxy or-C (O) OC 4H9.
Most preferably, the compound of formula I is selected from:
As used herein, "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound of interest and exhibits minimal undesirable toxicological effects. When the compounds of the present invention contain relatively acidic functional groups, the base addition salts may be obtained by contacting the neutral form of the compounds of the present invention with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable bases include inorganic bases and salts prepared from organic bases, wherein the salts of inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. The salts of organic non-toxic bases include salts of primary, secondary and tertiary amines, including substituted and cyclic amines. For example: n, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectate acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, and the like include sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, ethylenediamine, N-methylglucamine, and the like.
As used herein, "pharmaceutically acceptable esters" refer to esters of the-OH present in the compounds provided herein with an appropriate acid (e.g., carboxylic acid or oxygen-containing mineral acid). Suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, hard fatty acid ester, or palmitate.
As used herein, "isomer" means that where a compound of formula I contains one or more asymmetric centers and/or double bonds, the compounds of the present invention can exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, single diastereomers, geometric isomers, and the like. These compounds may be represented by the symbol "R" or "S", depending on the configuration of the substituents around the steric carbon atom, and may also be represented by the symbol "Z" or "E", depending on the arrangement of the substituents around the carbon-carbon double bond, or the substituents around the carbon-carbon double bond may be referred to as "cis" or "trans". The compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be included within the scope of the invention, even though only one tautomeric structure is depicted, such as keto-enol tautomer, phenol-keto tautomer, nitroso-oxime tautomer, imine-enamine tautomer, and the like.
As used herein, "polymorphic forms" means that a compound of formula I may also exist in various crystalline forms by recrystallizing the compound or a pharmaceutically acceptable salt thereof in a solvent to give different single crystalline forms as well as a mixture of polymorphic forms.
As used herein, "solvate" means that the compounds of formula I may exist in the form of solvates (e.g., hydrates) wherein the compounds of the present invention comprise a polar solvent as a structural element of the compound lattice, such as, inter alia, water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
As used herein, "isotope" refers to a compound of formula I and is also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, but with deuterium (2H) or tritium (3H) substituted for hydrogen, or 13C-or 14C-carbon atoms substituted for carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents.
As used herein, "prodrug" means that the compound of formula I may also be in the form of a prodrug or may be in a form that releases the active ingredient upon a metabolic change in the body. The selection and preparation of the appropriate prodrug derivatives is well known to those skilled in the art.
Subject matter II
The invention provides a pharmaceutical composition comprising a compound of a substituted benzoheterocycle structure shown in formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically labeled compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.
As used herein, a "pharmaceutical composition" comprises a therapeutically effective amount of a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically labeled compound, metabolite, or prodrug of said polysubstituted benzoheterocycle compound of formula I in combination with one or more pharmaceutically acceptable carriers, and is formulated as a tablet, capsule, granule, powder, suspension, emulsion, powder, solution, gel, syrup, pill, tincture, wine, plaster, lozenge, mixture, suppository, injection, inhalant or spray. The pharmaceutical composition preferably contains 0.1 to 99.5% by weight of the polysubstituted benzoheterocycle compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, more preferably contains 0.5 to 99.5% by weight of the active ingredient.
As used herein, "pharmaceutically acceptable carrier or excipient" includes: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity enhancing agents, antioxidants, preservatives, stabilizers, surfactants and buffers, it will be understood by those skilled in the art that certain pharmaceutically acceptable excipients may be used in more than one function and in alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example: when used orally, oral preparations such as tablets, capsules, granules, pills and the like can be made, containing fillers (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, acacia, dextran, silicate derivatives such as magnesium aluminum metasilicate, phosphate derivatives such as calcium phosphate, carbonate derivatives such as calcium carbonate, sulfate derivatives such as calcium sulfate and the like), binders (e.g., gelatin, polyvinylpyrrolidone, and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as carboxymethyl cellulose sodium, polyvinylpyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl parahydroxybenzoate, propyl parahydroxybenzoate and the like), flavoring agents (e.g., conventional sweeteners, sour agents, flavors and the like). When used parenterally, injections, including sterile powders for injection and solvents for injection, may be formulated with carriers or excipients including sterile water, ringer's solution and isotonic sodium chloride solution, and with appropriate additives such as antioxidants, buffers and bacteriostats, depending on the nature of the drug. When used for rectal administration, the medicament may be formulated as suppositories and the like. For pulmonary administration, the medicament may be formulated as an inhalant or spray, or the like. There are many sources available to those skilled in the art which describe pharmaceutically acceptable excipients and which can be used to select suitable pharmaceutically acceptable excipients, for example books such as Leimden pharmaceutical university, chinese pharmaceutical annual de-gress, pharmaceutics, etc.
The present invention may be administered by any suitable means known in the art, e.g., oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal administration, etc., and the compounds described above may be administered in any amount ranging from 1 μg to 2000mg per kg of subject body weight, e.g., from 1 μg to 1000mg per kg of body weight per day, from 50 μg to 1000mg per kg of body weight per day, from 100 μg to 1000mg per kg of body weight per day, from 1 to 500mg per kg of body weight per day, from 2 to 200mg per kg of body weight per day, from 5 to 100mg per kg of body weight per day. In some embodiments of the invention, the compounds described above may be administered 4 times daily, 3 times daily, 2 times daily, 1 time weekly, or at other intervals, optionally repeating the dosing regimen described above weekly or monthly as appropriate. In the present invention, the dosage of the compound to be administered may be adjusted according to the patient's or subject's condition, age, weight, sex, mode of administration, course of treatment, and the like.
The compounds of the present invention may be used alone or in combination with another one or more other active ingredients to treat, prevent, inhibit or ameliorate a disease or condition, wherein the combination of the agents is safer or more effective than the use of either agent alone. Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention in the routes and amounts commonly used therefor. When the compounds of the present invention are used simultaneously with one or more other drugs, pharmaceutical compositions containing the other drugs and the compounds of the present invention in unit dosage form are preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combination therapy may also include treatment with the compounds of the invention and one or more other drugs administered in different overlapping schedules. It is also contemplated that the compounds of the present invention and other active ingredients, when used in combination with one or more other active ingredients, may be used in lower dosages than when each is used alone. Thus, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention include those compositions containing one or more other active ingredients.
Subject III
The invention also provides application of the compound with the substituted benzo heterocyclic structure shown in the formula I, and pharmaceutically acceptable salts or esters, solvates, isomers, polymorphs, isotopically-labeled compounds, metabolites or prodrugs thereof in preparation of FOXM1 protein inhibitors or antitumor drugs.
The invention researches the affinity and anti-tumor activity of the compound shown in the formula I and the FOXM1 protein. Experiments prove that the compound XST20 shown as the formula I possibly affects the signal path through binding to the FOXM1 protein and inhibits cancer cell proliferation, and is used for treating tumor-related diseases.
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically-labeled compound, metabolite or prodrug thereof is for use in therapeutic treatment. In some embodiments of the invention, the therapeutic treatment is for treating a neoplastic disease. In some embodiments, neoplastic disease refers to localized tumors formed by abnormal proliferation of cells in the body under the influence of various causative factors, including benign tumors, malignant tumors, and borderline tumors. Including but not limited to breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
In some embodiments of the invention, methods of binding FOXM1 protein in vivo or in vitro are contemplated comprising the step of administering to a subject, mammalian cell an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically labeled compound, metabolite or prodrug thereof of any of the present invention.
In some embodiments of the invention, methods of inhibiting FOXM1 activity in vivo or in vitro are contemplated comprising the step of administering to a subject, mammalian cell an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotopically labeled compound, metabolite or prodrug thereof of any of the present invention.
Advantageous effects of the invention
Through extensive research and screening, the inventor of the present application found a series of FOXM1 inhibitors, which can exert antitumor activity by inhibiting FOXM1 to down-regulate the level of its downstream target protein. The series of compounds can therefore be used for the prophylaxis and/or treatment of neoplastic diseases.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments will be briefly described below.
FIG. 1 is a graph showing the change in body weight of 21-day mice;
FIG. 2 is a graph showing tumor volume change in 21-day mice;
FIG. 3 is the tumor fluorescence area of mice;
FIG. 4 is a graph of tumor weight in mice;
FIG. 5 is a graph showing the Western blot detection of the expression levels of the target protein downstream of FOXM1 in mouse tumor tissues.
Detailed Description
The following description sets forth the invention in connection with specific examples which are not intended to limit the scope of the invention, but are presented to provide those skilled in the art with a guide in the preparation and use of the compounds, compositions, and methods of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The chemical names of the compounds described in the present application are generally from ChemDraw Ultra (ChambridgeSoft) and the principles of IUPAC nomenclature are generally followed.
The compounds of formula I of the present invention can be prepared by the following preparation schemes, it will be appreciated by those skilled in the art that to obtain the various compounds of the present invention, the starting materials may be appropriately selected such that the final desired substitution, with or without protection, is made by the reaction scheme to yield the desired product. Furthermore, those skilled in the art will recognize that the following routes will be helpful in understanding the present invention, but are not limiting of the invention:
route one: synthetic route represented by C series compound
Reaction conditions: a) K 2CO3,KI,DMF,90℃;b)CBr4,PPh3, THF, reflux; c) K 2CO3, KI, THF, reflux; d) TFA, DCM, r.t.
Route two: synthetic routes represented by B and S series compounds
Reaction conditions: a) Pd/C, H 2,EtOH,50psi,r.t;b)K2CO3, KI, DMF,90 ℃; c) NaOH, meOH, reflux; d) Pd/C, H 2, meOH, r.t.
Route four: synthetic route represented by N series of compounds
Reaction conditions: a) Cyclopentanol, K 2CO3, KI, THF, reflux.
Route five: synthetic route represented by O series compound
Reaction conditions: a) K 2CO3,KI,DMF,90℃;b)CBr4,PPh3, THF, reflux; c) Cyclopentane, K 2CO3, KI, THF, reflux.
Route eight: synthetic route represented by O2
Reaction conditions: a) Epichlorohydrin, TBAB, naOH, H 2 O,50 ℃; b) Cyclopentane, DMF,100 ℃.
The following is a description of specific examples.
Example 1
2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethanol (2 a)
4-Benzyloxyphenol (6.06 g,30 mmol), K 2CO3 (16.56 g,120 mmol) and KI (4.98 g,30 mmol) were dissolved in 150mL anhydrous DMF under nitrogen and heated with stirring for several minutes. A solution of 2- (2-chloroethoxy) ethanol (6.4 mL,60 mmol) in anhydrous DMF (30 mL) was added to the reaction mixture and heated to 90℃for overnight reaction. TLC detection, reaction was essentially complete. Stopping heating and naturally cooling the reaction solution to room temperature. The filtrate was collected by filtration, and concentrated under reduced pressure to evaporate DMF. Diluted with DCM, washed with distilled water (100 mL), saturated brine (100 mL), the organic layer was separated, dried overnight with appropriate amount of anhydrous sodium sulfate, filtered with suction, and the solvent was spun-dried. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 2a 5.18g of white crystals in yield 60％,mp:79.0-80.2℃.1H NMR(400MHz,DMSO-d6)δ:7.43(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(d,J＝7.2Hz,1H), 6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.61(t,J＝5.4Hz,1H),4.01(t,J＝5.4Hz,2H),3.70(t,J＝5.4Hz,2H),3.51-3.47(m,4H).13C NMR(126MHz,CDCl3)δ:153.4,153.1,137.4, 128.8,128.1,127.7,116.0,115.8,72.7,70.8,70.0,68.2,62.0.
Example 2
1- (2- (2-Bromoethoxy) ethoxy) -4-benzyloxybenzene (3 a)
Ca (1.44 g,5 mmol) and triphenylphosphine (2.63 g,10 mmol) were dissolved in 40mL anhydrous THF under nitrogen. CBr4 (3.4 g,10 mmol) in anhydrous THF (10 mL) was added to the reaction solution, stirred at room temperature and reacted immediately with white precipitate, after which the reaction turned yellow and then green, and monitored by TLC for completion of the reaction for 1 h. Adding 15mL of ethyl acetate into the reaction solution, precipitating impurities, filtering the reaction solution, filtering triphenylphosphine oxide impurities, collecting filtrate, and evaporating the solvent to obtain a crude product. Separating the crude product by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to obtain white crystal 3a 1.48g, with yield 85%, mp 58.5-59.3deg.C; MS (ESI) m/z 352[ M+H ] +.
Example 3
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (XST 20)
Cyclopentylamine (182. Mu.L, 2 mmol), K2CO3 (1.90 g,13.8 mmol) and KI (760 mg,4.6 mmol) were dissolved in 70mL anhydrous DMF under nitrogen. Intermediate 3a (1.6 g,4.6 mmol) was added thereto and heated to 80 ℃ for reaction. TLC detection shows that the starting material was not completely reacted for 5h, and that a part of the starting material remained for 18 h. Stopping heating and naturally cooling the reaction solution to room temperature. The filtrate was collected by filtration, and concentrated to evaporate the solvent. The residue was dissolved in EA, washed with distilled water and saturated brine, dried over anhydrous Na2SO4, filtered and spun-dried to give the crude product. After separation by silica gel column chromatography (ethyl acetate: ethanol: triethylamine=10:1:0.001), light brown solid XST 20.28 g was obtained in yield 78％, mp:33.1-34.9℃.1H NMR(400MHz,DMSO-d6)δ:7.42(d,J＝6.8Hz,2H),7.37(t,J＝8.0Hz,2H), 7.33-7.29(m,1H),6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.02-4.00(m,2H),3.69-3.66(m,2H),3.49(t,J＝6.0Hz,2H),3.00-2.93(m,1H),2.63(t,J＝5.6Hz,2H),1.72-1.53(m,4H), 1.48-1.39(m,2H),1.28-1.19(m,2H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.6,115.3,70.3,69.6,68.8,67.4,59.2,47.4,32.6,23.6.
Example 4
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) cyclopropylamine (C1)
Starting with cyclopropylamine, brown oily C1 is obtained according to the preparation method of compound XST20, and the yield is 18％.1H NMR(500 MHz,DMSO-d6)δ:7.42(d,J＝7.5Hz,2H),7.38(t,J＝7.5Hz,2H),7.31(t,J＝7.5Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.68(t,J＝4.5Hz,2H),3.49(t,J ＝5.5Hz,2H),2.71(t,J＝5.5Hz,2H),2.09-2.05(m,1H),0.35-0.31(m,2H),0.18-0.16(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3,70.0,69.6,68.8,67.5, 48.4,30.0,6.1.
Example 5
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) cyclobutylamine (C2)
The brown solid C2 is obtained by taking the cyclobutylamine as a raw material according to the preparation method of the compound XST20, and the yield is 35％,mp:37.2-38.5℃. 1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.93(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.67(t,J＝4.5Hz, 2H),3.46(t,J＝6.0Hz,2H),3.17-3.11(m,1H),2.58(t,J＝6.0Hz,2H),2.09-2.03(m,2H),1.64-1.50(m,4H).13C NMR(101MHz,DMSO-d6)δ:152.7,152.4,137.4,128.4,127.8,127.7,115.7,115.3,70.2,69.6, 68.9,67.4,53.7,45.8,30.5,14.4.
Example 6
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) cyclohexylamine (C3)
The cyclohexylamine is used as a raw material, and the pale yellow solid C3 is obtained according to the preparation method of the compound XST20, and the yield is 53％,mp:58.7-59.8℃. 1H NMR(400MHz,DMSO-d6)δ:7.43(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H), 6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.01(t,J＝4.8Hz,2H),3.68(t,J＝4.8Hz,2H),3.49(t,J＝5.6Hz,2H),2.67(t,J＝5.6Hz,2H),2.36-2.29(m,1H),1.78-1.74(m,2H),1.66-1.61(m, 2H),1.54-1.50(m,1H),1.23-1.08(m,3H),1.00-0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3,70.4,69.6,68.8,67.5,56.0,45.8,33.0,25.9,24.4.HRMS (ESI):calcd for C23H32O3N[M+H]+,370.2377,found 370.2371.
Example 7
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) cycloheptylamine (C4)
The C4 brown oily matter is obtained by taking cycloheptylamine as a raw material according to the preparation method of the compound XST20, and the yield is 23％.1H NMR(400 MHz,DMSO-d6)δ:7.42(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝ 9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.03(s,2H),4.02-4.00(m,2H),3.69-3.66(m,2H),3.49(t,J＝5.6Hz,2H),2.64(t,J＝5.6Hz,2H),2.58-2.52(m,1H),1.74-1.68(m,2H),1.60-1.53(m,2H),1.51-1.42(m,4H), 1.38-1.22(m,4H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3,70.3,69.6,68.8,67.5,58.0,46.3,34.2,28.0,23.7.
Example 8
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) aniline (C5)
Using aniline as raw material, obtaining brown solid C5 according to the preparation method of compound XST20, and obtaining the yield 46％.mp:47.9-49.1℃.1H NMR(400MHz,DMSO-d6)δ:7.42(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H), 7.05(t,J＝7.2Hz,2H),6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),6.57(d,J＝7.6Hz,2H),6.52(t,J＝7.2Hz,1H),5.49(s,1H),5.03(s,2H),4.03(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.61(t,J＝5.6Hz, 2H),3.19(t,J＝5.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ:153.1,152.9,149.1,137.8,129.4(2), 128.8(2),128.2,128.1(2),116.2,116.1(2),115.8(2),112.5(2),70.1,69.6,69.4,68.0,43.1.
Example 9
N-2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl-4-pyridinamine (C6)
The compound 4-aminopyridine is taken as a raw material, and light yellow solid C6 is obtained according to the preparation method of the compound XST20, and the yield is high 22％, mp:120.7-122.3℃.1H NMR(400MHz,DMSO-d6)δ:7.24-1.18(m,2H),6.62-6.49(m,5H),6.11-6.09(m,2H),6.00-5.93(m,4H),4.21(s,2H),3.50-3.48(m,2H),3.20-3.19(m,2H),3.08-3.06(m,2H),2.98- 2.96(m,2H).13C NMR(105MHz,DMSO-d6)δ:151.3,145.1,144.9,135.0,129.4,120.0,119.3,119.1,107.4,107.0,100.9,62.1,61.4,61.2,59.6,49.4.
Example 10
3- (N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) amino) tetrahydrofuran (C7)
The compound 3-aminotetrahydrofuran is taken as a raw material, and light yellow oily C7 is obtained according to the preparation method of the compound XST20, and the yield is 39％.1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0 Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.68(m, 4H),3.62(dd,J＝5.5,8.0Hz,1H),3.49(t,J＝5.5Hz,2H),3.36(dd,J＝4.0,4.5Hz,1H),3.26(m,1H),2.65(m,2H),1.91(m,1H),1.59(m,1H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4(2), 127.7,127.6(2),115.7(2),115.3(2),72.6,70.3,69.6,68.9,67.4,66.4,58.1,47.3,32.6.
Example 11
3- ((2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethyl) amino) -1-pyrrolidinecarboxylic acid tert-butyl ester (C8)
The compound 3-aminopyrrolidine-1-tert-butyl formate is taken as a raw material, and light yellow oily C8 is obtained according to the preparation method of the compound XST20, and the yield is obtained 76％.1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝9.5Hz,2H),7.38(t,J＝9.0Hz,2H),7.31(t, J＝9.0Hz,1H),6.92(d,J＝10.0Hz,2H),6.86(d,J＝10.0Hz,2H),5.03(s,2H),4.02(m,2H),3.69-3.68(m,2H),3.49(t,J＝6.5Hz,2H),3.28-3.24(m,1H),3.19-3.13(m,2H),2.94(dd,J＝5.5,13.5Hz,1H), 2.70-2.62(m,2H),1.90-1.86(m,2H),1.64-1.56(m,1H),1.38(s,11H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.6,115.3,78.0,70.3,69.6,68.8,67.4,57.2,56.4,51.6,51.4, 46.9,44.2,44.0,31.3,30.6,28.2.
Example 12
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -3-pyrrolidinamine (C9)
C8 (250 mg,0.55 mmol) was added to DCM (5 mL) and trifluoroacetic acid (340. Mu.L, 4.4 mmol) was added and the reaction stirred at room temperature. The reaction was monitored by TLC, 6h reaction completed and the reaction was evaporated to dryness. After dilution with DCM (10 mL), the mixture was evaporated to dryness again and the procedure was repeated once. DCM (4 mL) and 1N HCl (4 mL) were then added and the pH was adjusted to around 9 with 1N NaOH, and a solid appeared. Spin-drying solvent, dissolving with methanol, diluting, filtering, collecting filtrate, spin-drying methanol, and vacuum drying the residue to obtain brown yellow oily substance C9 52mg, yield 26％.1H NMR(500MHz,CD3OD)δ:7.41(d,J＝7.5Hz,2H),7.36(t,J＝7.5Hz,2H),7.30(t,J＝ 7.5Hz,1H),6.92(d,J＝9.0Hz,2H),6.87(d,J＝9.0Hz,2H),5.02(s,2H),4.11(t,J＝4.5Hz,2H),3.86(t,J＝4.5Hz,2H),3.80(t,J＝5.0Hz,2H),3.24(t,J＝5.0Hz,2H),3.10-3.05(m,1H),2.10-2.05(m,2H), 1.90-1.84(m,2H),1.34-1.31(m,2H).13C NMR(126MHz,CD3OD)δ:154.8,154.4,139.1,129.6,129.0,128.7,117.2,116.6,71.7,71.2,69.3,67.5,58.4,45.6,30.4,26.2,25.6.
Example 13
2- (2- ((2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethyl) amino) ethoxy) ethanol (C10)
The compound 2-aminoethoxyethanol is taken as a raw material, and the pale yellow oily C10 is obtained according to the preparation method of the compound XST20, and the yield is 10％.1H NMR(500MHz,DMSO-d6)δ:7.43(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0 Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.01(t,J＝4.5Hz,2H),3.68(t,J＝4.5Hz,2H),3.50(t,J＝5.5Hz,2H),3.47(t,J＝5.0Hz,2H),3.44(t,J＝5.5Hz,2H),3.38(t,J＝5.0Hz, 2H),2.68-2.64(m,4H).13C NMR(101MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7, 115.3,72.2,69.6,69.6,69.4,68.9,67.4,60.2,48.5,48.4.
Example 14
2- (2- (4- (Benzyloxy) phenoxy) ethoxy) -N, N-dimethylethylamine (C11)
The colorless oily substance C11 is obtained by taking dimethylamine as a raw material according to the preparation method of XST20, and the yield is 35％.1H NMR (500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d, J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.00(t,J＝4.5Hz,2H),3.68(t,J＝4.5Hz,2H),3.53(t,J＝6.0Hz,2H),2.43(t,J＝6.0Hz,2H),2.16(s,6H).13C NMR(126MHz,DMSO-d6)δ:152.6,152.4, 137.4,128.4,127.8,127.7,115.7,115.3,69.6,68.9,68.6,67.5,58.3,45.6.
Example 15
4- (2- (2- (Cyclopentylamino) ethoxy) phenol (4 a)
Compound XST20 (1.85 g,5 mmol) was dissolved in dry methanol (100 mL) to give a gold concentration of 0.05M for flow hydrogenation, and the reaction was carried out in a flow hydrogenation apparatus (set in normal temperature and pressure full H 2 mode, flow rate 1mL/min, pd/C column catalysis). TLC monitoring reaction, once-through reaction, spin-drying solvent to obtain white solid 4a1.3g, yield 98％,mp:106.3-107.5℃.1H NMR(400MHz, DMSO-d6)δ:8.90(s,1H),6.74(d,J＝9.2Hz,2H),6.65(d,J＝9.2Hz,2H),3.96(t,J＝4.8Hz,2H),3.66(t, J＝4.8Hz,2H),3.48(t,J＝6.4Hz,2H),2.96(m,1H),2.63(t,J＝4.8Hz,2H),1.67(m,2H),1.58(m,2H),1.44(m,2H),1.24(m,2H).13C NMR(126MHz,CDCl3)δ:152.2,151.3,116.4,116.0,70.1,69.9,67.9, 60.1,48.06,32.7,24.2.
Example 16
N- (2- (2- (4- ((4-methoxybenzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B1)
4A (100 mg,0.38 mmol), K 2CO3 (159 mg,1.14 mmol) and KI (63 mg,0.38 mmol) were dissolved in 5mL anhydrous DMF under nitrogen and heated with stirring for several minutes. A solution of 4-methoxybromobenzyl (89. Mu.L, 0.57 mmol) in anhydrous DMF (2 mL) was added to the reaction mixture, and the reaction was stirred at room temperature. TLC detection, 12h reaction was complete. The reaction solution was filtered, and the filtrate was collected, washed with distilled water (20 mL), saturated brine (20 mL), the organic layer was separated, dried overnight with an appropriate amount of anhydrous sodium sulfate, suction-filtered, and the solvent was dried. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate: triethylamine=3:1:0.001) to give B1 as a pale yellow oil, 120mg, yield 82％.1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.21(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),6.72(d,J ＝9.2Hz,2H),6.64(d,J＝9.2Hz,2H),3.92(t,J＝4.4Hz,2H),3.71(s,3H),3.59(t,J＝4.8Hz,2H),3.54(s,2H),3.42(t,J＝6.4Hz,2H),3.06(m,1H),2.58(t,J＝6.4Hz,2H),1.70(m,2H),1.57(m,2H),1.41(m, 4H).13C NMR(101MHz,DMSO-d6)δ:158.1,151.4,151.3,132.4,129.6,115.7,115.4,113.5,69.3,69.0, 67.6,63.1,55.6,55.0,50.1,28.9,23.9.
Example 17
N- (2- (2- (4- ((4-methylbenzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B2)
The white oily matter B2 is obtained by taking the compound 4-methyl bromobenzyl as a raw material according to the preparation method of the compound B1, and the yield is high 42％.1H NMR (400MHz,DMSO-d6)δ:8.88(s,1H),7.18(d,J＝7.6Hz,2H),7.07(d,J＝7.6Hz,2H),6.71(d,J＝9.2Hz, 2H),6.65(d,J＝9.2Hz,2H),3.90(t,J＝4.8Hz,2H),3.58(t,J＝4.8Hz,2H),3.57(s,2H),3.43(t,J＝6.4Hz,2H),3.07(m,1H),2.58(t,J＝6.4Hz,2H),2.26(s,3H),1.70(m,2H),1.57(m,2H),1.38(m,4H).13C NMR(101MHz,DMSO-d6)δ:151.3,151.2,137.5,135.4,128.6,128.4,115.7,115.34,69.3,69.0,67.6, 63.2,55.9,50.2,28.8,23.8,20.7..
Example 18
N- (2- (2- (4- ((4- (benzyloxy) benzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B3)
The compound 4-benzyloxy bromobenzyl is taken as a raw material, and light yellow oily matter B3 is obtained according to the preparation method of the compound B1, and the yield is obtained 48％.1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.43(d,J＝6.8Hz,2H),7.38(t,J＝6.8Hz,2H),7.31(t,J＝ 7.6Hz,1H),7.21(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),6.72(d,J＝9.2Hz,2H),6.65(d,J＝9.2Hz,2H),5.05(s,2H),3.91(t,J＝4.8Hz,2H),3.59(t,J＝4.8Hz,2H),3.54(s,2H),3.42(t,J＝6.4Hz,2H), 3.07(m,1H),2.58(t,J＝6.4Hz,2H),1.70(m,2H),1.56(m,2H),1.40(m,4H).13C NMR(101MHz, DMSO-d6)δ:157.1,151.3,151.2,137.2,132.6,129.5,128.4,127.8,127.7,115.7,115.4,114.3,69.3,69.1, 69.0,67.6,63.1,55.5,50.1,28.8,23.8.1-67.
Example 19
N- (2- (2- (4- ((4-chlorobenzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B4)
The compound 4-chlorobenzyl bromide is taken as a raw material, the brown yellow oily matter B4 is obtained according to the preparation method of the compound B1, and the yield is obtained 30％.1H NMR (400MHz,DMSO-d6)δ:8.89(s,1H),7.35-7.30(m,4H),6.72-6.69(m,2H),6.67-6.64(m,2H),3.92-3.90 (m,2H),3.61(s,2H),3.60-3.58(m,2H),3.44(t,J＝6.4Hz,2H),3.11-3.03(m,1H),2.60(t,J＝6.4Hz,2H),1.74-1.67(m,2H),1.58-1.53(m,2H),1.45-1.32(m,4H).13C NMR(101MHz,DMSO-d6)δ:151.3, 151.2,140.0,130.9,130.0,127.9,115.7,115.4,69.3,69.0,67.6,63.4,55.3,50.6,28.8,23.8.
Example 20
4- ((Methyl 4- (2- (2- (2- (cyclopentylamino) ethoxy) phenoxy) methyl) benzoate (B5)
The brown oily matter B5 is obtained by taking the compound 4-bromomethyl benzoate as a raw material according to the preparation method of the compound B1, and the yield is 55％.1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.87(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),6.70(d,J ＝8.8Hz,2H),6.64(d,J＝8.8Hz,2H),3.90(t,J＝4.4Hz,2H),3.83(s,3H),3.71(s,2H),3.58(t,J＝4.4Hz,2H),3.45(t,J＝6.4Hz,2H),3.09(m,1H),2.63(t,J＝6.4Hz,2H),1.71(m,2H),1.57(m,2H),1.39(m, 4H).13C NMR(101MHz,DMSO-d6)δ:166.3,151.3,151.3,147.2,129.0,128.5,128.0,115.7,115.4,69.3, 69.0,67.6,63.8,55.9,52.1,51.1,28.9,23.8.
Example 21
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzoic acid (B6)
B5 (300 mg,0.74 mmol) was dissolved in methanol (15 mL) and a 1N NaOH solution (1.5 mL,1.5 mmol) was added and the mixture was heated at reflux. TLC monitoring, 20h reaction was complete. Stopping heating, naturally cooling the reaction liquid to room temperature, filtering the reaction liquid, collecting filtrate and spin-drying. The residue was dissolved in a small amount of distilled water and the pH was adjusted to 2-3 with 1N HCl until a solid had precipitated. Evaporating the solvent, dissolving in methanol, filtering, collecting filtrate, spin-drying, and vacuum drying the residue to obtain pale pink solid B6 110mg, yield 30％,mp:199.1- 201.9℃.1H NMR(400MHz,CD3OD)δ:8.08(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),6.79(d,J＝4.8 Hz,2H),6.71(d,J＝4.8Hz,2H),4.57(s,2H),4.10(t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H),3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).13C NMR(101 MHz,CD3OD)δ:169.0,153.4,152.9,136.1,133.6,132.8,131.6,117.1,116.8,71.3,69.3,67.1,66.3,57.7, 51.5,29.1,25.3.
Example 22
3- ((Methyl 4- (2- (2- (2- (cyclopentylamino) ethoxy) phenoxy) methyl) benzoate (B7)
The compound 3-bromomethyl benzoate is taken as a raw material, and the pale yellow solid B7 is obtained according to the preparation method of the compound B1, and the yield is obtained 96％, mp:73.6-75.0℃.1H NMR(500MHz,DMSO-d6)δ:8.87(s,1H),7.93(s,1H),7.80(d,J＝7.5Hz,1H), 7.60(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),6.70(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.90(t,J＝4.5Hz,2H),3.83(s,2H),3.57(t,J＝4.5Hz,2H),3.45(t,J＝6.0Hz,2H),3.10(m,1H),2.63(t,J＝6.0 Hz,2H),1.72(m,2H),1.58(m,2H),1.40(m,4H).13C NMR(101MHz,DMSO-d6)δ:166.4,151.2,151.2, 141.9,133.2,129.4,128.9,128.4,127.4,115.6,115.4,69.2,68.9,67.5,63.5,55.6,52.1,50.7,28.9,23.8.
Example 23
3- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzoic acid (B8)
Using the compound B7 as a raw material, obtaining pink solid B8 according to the preparation method of the compound B6, and obtaining the yield 30％,mp:209.1-211.7℃.1H NMR(400MHz,CD3OD)δ:8.21(s,1H),8.09(d,J＝7.6Hz,1H),7.78(d,J＝7.6Hz,1H),7.53(t,J＝ 7.6Hz,1H),6.76(d,J＝9.2Hz,2H),6.68(d,J＝9.2Hz,2H),4.54(s,2H),4.10-4.07(m,2H),3.89-3.86(m,1H),3.83-3.79(m,4H),3.37-3.34(m,2H),2.20-2.15(m,2H),1.89-1.79(m,4H),1.71-1.60(m,2H).13C NMR(101MHz,CD3OD)δ:169.42,153.41,152.91,136.72,133.95,133.57,132.25,131.86,130.64, 117.05,116.91,71.31,69.32,66.96,66.38,57.82,51.46,29.26,25.35.
Example 24
Methyl 2- ((4- (2- (2- (cyclopentylamino) ethoxy) phenoxy) methyl) benzoate (B9)
The compound 2-bromomethyl benzoate is taken as a raw material, and light yellow oily matter B9 is obtained according to the preparation method of the compound B1, and the yield is obtained 98％.1H NMR(500MHz,CD3OD)δ:8.91(s,1H),7.62(t,J＝9.0Hz,2H),7.46(t,J＝7.5Hz,1H),7.31 (t,J＝7.5Hz,1H),6.70(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.89-3.87(m,4H),3.78(s,3H),3.53(t,J＝4.5Hz,2H),3.34-3.32(m,2H),3.08-3.02(m,1H),2.57(t,J＝6.5Hz,2H),1.68-1.65(m,2H), 1.58-1.52(m,2H),1.43-1.39(m,2H),1.36-1.29(m,2H).13C NMR(101MHz,DMSO-d6)δ:168.2,151.2, 151.2,141.3,131.1,130.7,129.6,128.9,126.6,115.6,115.4,69.1,68.9,67.5,63.8,54.6,51.9,50.8,28.4,23.7.
Example 25
2- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzoic acid (B10)
Using the compound B9 as a raw material, obtaining pink solid B10 according to the preparation method of the compound B6, and obtaining the yield 38％,mp:221.3-224.7℃.1H NMR(400MHz,CD3OD)δ:8.08(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),6.79(d,J＝4.8Hz,2H), 6.71(d,J＝4.8Hz,2H),4.57(s,2H),4.10(t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H),3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).13C NMR(101MHz, CD3OD)δ:174.6,153.6,152.7,139.5,134.2,133.0,132.3,131.3,131.2,117.0,116.9,71.2,69.3,66.7,66.5, 58.8,51.2,28.9,25.1.
Example 26
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzaldehyde (B11)
The compound 4-bromomethylbenzaldehyde is taken as a raw material, light yellow oily matter B11 is obtained according to the preparation method of the compound B1, and the yield is improved 75％.1H NMR(500MHz,DMSO-d6)δ:9.95(s,1H),8.88(s,1H),7.82(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz, 2H),6.70(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.91(t,J＝4.5Hz,2H),3.74(s,2H),3.58(t,J＝4.5 Hz,2H),3.47(t,J＝6.0Hz,2H),3.10(m,1H),2.64(t,J＝6.0Hz,2H),1.72(m,2H),1.57(m,2H),1.40(m,4H).13C NMR(126MHz,DMSO-d6)δ:151.3,151.3,148.8,135.0,129.4,128.8,115.7,115.4,69.5,69.0, 67.6,63.8,56.0,51.1,28.9,23.8.
Example 27
N- (2- (2- (4- ((4-nitrobenzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B12)
The compound p-nitrobenzyl bromide is taken as a raw material, light yellow oily matter B12 is obtained according to the preparation method of the compound B1, and the yield is high 49％.1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),8.13(d,J＝8.5Hz,2H),7.61(d,J＝8.5Hz,2H),6.70(d,J ＝8.5Hz,2H),6.64(d,J＝8.5Hz,2H),3.91(t,J＝4.5Hz,2H),3.77(s,2H),3.58(t,J＝4.5Hz,2H),3.47(t,J＝6.0Hz,2H),3.10(m,1H),2.65(t,J＝6.0Hz,2H),1.72(m,2H),1.57(m,2H),1.43(m,2H),1.34(m, 2H).13C NMR(101MHz,DMSO-d6)δ:151.3,151.3,150.1,146.3,129.2,123.2,115.7,115.4,69.4,69.1, 67.6,64.0,55.6,51.4,29.0,23.8.
Example 28
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) aniline (B13)
Compound B12 (150 mg,0.39 mmol) was dissolved in methanol (9.5 mL) to give a gold concentration of 0.05M for flow hydrogenation, and the reaction was carried out using a flow hydrogenation apparatus (set in normal temperature and pressure full H 2 mode, flow rate 1mL/min, pd/C column catalysis). TLC monitored the reaction, once complete, spin-dry the solvent. The residue is chromatographed on a silica gel column to obtain brown solid B13 mg, yield 45％,mp:110.0- 112.2℃.1H NMR(400MHz,DMSO-d6)δ:8.88(s,1H),6.93(d,J＝7.6Hz,2H),6.72(d,J＝8.8Hz,2H), 6.64(d,J＝8.8Hz,2H),6.48(d,J＝7.6Hz,2H),4.87(s,2H),3.91(s,2H),3.59(s,2H),3.41(m,4H),3.05(m,1H),2.55(t,J＝6.4Hz,2H),1.70(m,2H),1.56(m,2H),1.39(m,4H).
Example 29
N- (2- (2- (4- ((3-nitrobenzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B14)
The compound 3-nitrobenzyl bromide is taken as a raw material, and light yellow oily matter B14 is obtained according to the preparation method of the compound B1, and the yield is obtained 82％.1H NMR(500MHz,DMSO-d6)δ:8.87(s,1H),8.20(s,1H),8.06(d,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H), 7.57(t,J＝8.0Hz,1H),6.69(d,J＝9.0Hz,2H),6.63(d,J＝9.0Hz,2H),3.91(t,J＝4.5Hz,2H),3.78(s,2H),3.58(t,J＝4.5Hz,2H),3.48(t,J＝6.0Hz,2H),3.12(m,1H),2.66(t,J＝6.0Hz,2H),1.73(m,2H), 1.58(m,2H),1.44(m,2H),1.36(m,2H).13C NMR(101MHz,DMSO-d6)δ:151.2,151.2,147.8,144.0, 134.8,129.4,122.5,121.5,115.6,115.3,69.2,69.0,67.5,63.7,55.0,51.1,28.9,23.7.
Example 30
3- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) aniline (B15)
The compound B14 is used as a raw material, the pale yellow oily matter B15 is obtained according to the preparation method of the compound B13, and the yield is high 27％.1H NMR (400MHz,DMSO-d6)δ:8.88(s,1H),6.90(t,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,2H),6.65(d,J＝7.6Hz,2H),6.55(s,1H),6.44(d,J＝7.6Hz,1H),6.39(d,J＝7.6Hz,1H),4.93(s,2H),3.92(s,2H),3.60(s,2H), 3.44(m,4H),3.08(m,1H),2.58(t,J＝7.0Hz,2H),1.72(m,2H),1.57(m,2H),1.40(m,4H).13C NMR (101MHz,DMSO-d6)δ:151.4,151.3,148.5,141.2,128.5,116.2,115.8,115.5,114.0,112.4,69.3,69.1,67.7,63.2,56.6,50.3,28.8,23.9.
Example 31
N- (2- (2- (4- ((2-nitrobenzyl) oxy) phenoxy) ethoxy) ethyl) cyclopentylamine (B16)
The compound 2-nitrobenzyl bromide is taken as a raw material, and light yellow oily matter B16 is obtained according to the preparation method of the compound B1, and the yield is obtained 93％.1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.83(d,J＝8.0Hz,1H),7.78(d,J＝7.5Hz,1H),7.62(t,J＝8.0Hz,1H),7.47(t,J＝7.5Hz,1H),6.70(d,J＝9.0Hz,2H),6.63(d,J＝9.0Hz,2H),3.91(s,2H),3.88(t, J＝4.5Hz,2H),3.53(m,J＝4.5Hz,2H),3.36(t,J＝6.0Hz,2H),3.04(m,1H),2.60(t,J＝6.0Hz,2H),1.66(m,2H),1.55(m,2H),1.42(m,2H),1.30(m,2H).13C NMR(101MHz,DMSO-d6)δ:151.3,151.3, 149.4,135.5,132.6,131.1,128.1,123.9,115.7,115.4,69.1,69.0,67.6,64.0,53.3,51.1,28.5,23.6.
Example 32
2- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) aniline (B17)
Using the compound B16 as a raw material, obtaining yellow oily matter B17 according to the preparation method of the compound B13, and obtaining the yield 10％.1H NMR(500 MHz,DMSO-d6)δ:8.91(s,1H),6.95(t,J＝7.0Hz,2H),6.73(d,J＝9.0Hz,2H),6.65(d,J＝9.0Hz,2H), 6.57(d,J＝8.5Hz,1H),6.47(t,J＝7.0Hz,1H),5.28(s,2H),3.92(t,J＝4.5Hz,2H),3.58(t,J＝4.5Hz,2H),3.54(s,2H),3.46(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.56(t,J＝6.0Hz,2H),1.74-1.64(m,2H), 1.60-1.52(m,2H),1.47-1.37(m,4H).13C NMR(126MHz,DMSO-d6)δ:151.3,151.2,147.9,129.9,127.8, 122.3,115.8,115.7,115.4,114.5,68.9,68.7,67.5,62.5,55.8,49.1,27.9,23.8.
Example 33
1- (Benzyloxy) -4- (2- (2- (cyclopentyloxy) ethoxy) benzene (N1)
Taking cyclopentanol as a raw material, obtaining light yellow oily matter N1 according to a preparation method of XST20, and obtaining the yield 15％.1H NMR (500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d, J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.00(t,J＝4.5Hz,2H),3.88-3.87(m,1H),3.69(t,J＝4.5Hz,2H),3.54(t,J＝5.0Hz,2H),3.45(t,J＝5.0Hz,2H),1.66-1.62(m,2H),1.59-1.54(m,4H), 1.48-1.44(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3, 80.7,70.1,69.6,69.0,67.5,31.8,23.1.
Example 34
6- (4- (Benzyloxy) phenoxy) -1-hexanol (2 m)
The compound 4-benzyloxy phenol and 6-chloro-1-hexanol are used as raw materials, and light yellow solid 2m is obtained according to the preparation method of the compound 2a, and the yield is 55％,mp:94.9-96.8℃.MS(ESI)m/z:301[M+H]+.1H NMR(400MHz,DMSO-d6)δ:7.44-7.41(m, 2H),7.40-7.36(m,2H),7.33-7.29(m,1H),6.93-6.90(m,2H),6.85-6.82(m,2H),5.03(s,2H),4.33(t,J＝5.2Hz,1H),3.87(t,J＝6.8Hz,2H),3.40-3.36(m,2H),1.70-1.63(m,2H),1.46-1.30(m,6H).
Example 35
1-Benzyloxy-4- ((6-bromohexyl) oxy) benzene (3 m)
The compound 2m is taken as a raw material, and light yellow solid 3m is obtained according to the preparation method of the compound 3a, and the yield is 99％,mp:78.1-79.4℃. MS(ESI)m/z:364[M+H]+.1H NMR(400MHz,DMSO-d6)δ:7.44-7.41(m,2H),7.40-7.36(m,2H), 7.33-7.29(m,1H),6.93-6.90(m,2H),6.85-6.83(m,2H),5.03(s,2H),3.88(t,J＝6.4Hz,2H),3.53(t,J＝6.4Hz,2H),1.85-1.78(m,2H),1.71-1.64(m,2H),1.43-1.41(m,4H).
Example 36
N- (6- (4- (benzyloxy) phenoxy) hexyl) cyclopentylamine (O1)
Taking compound 3m and cyclopentylamine as raw materials, obtaining pale yellow solid O1 according to the preparation method of compound XST20, and obtaining the yield 52％, mp:51.2-53.3℃.1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31 (t,J＝7.0Hz,1H),6.91(d,J＝9.0Hz,2H),6.83(d,J＝9.0Hz,2H),5.03(s,2H),3.87(t,J＝6.5Hz,2H),2.97-2.93(m,1H),2.45(t,J＝6.5Hz,2H),1.66-1.65(m,4H),1.58-1.58(m,2H),1.44-1.32(m,8H), 1.26-1.23(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.9,152.3,137.4,128.4,127.7,127.6,115.7, 115.2,69.6,67.8,59.3,47.8,32.3,29.5,28.8,26.6,25.5,23.6.HRMS(ESI):calcd for C24H34O2N[M+H]+, 368.2584,found 368.2581.
Example 37
2- ((4- (Benzyloxy) phenoxy) methyl) oxirane (5)
4-Benzyloxyphenol (1.45 g,7 mmol) and NaOH (0.84 g,21 mmol) were dissolved in 30mL H 2 O and stirred at room temperature for 0.5H. The reaction was added dropwise to a 50mL round bottom flask containing epichlorohydrin (1.64 mL,21 mmol) and tetrabutylammonium bromide (112 mg,0.35 mmol), and heated to 50deg.C for reaction overnight. TLC detection, reaction was essentially complete. Stopping heating and naturally cooling the reaction solution to room temperature. Extracted with EA (20 mL. Times.3), the organic phases were combined, dried overnight with the addition of an appropriate amount of anhydrous sodium sulfate, filtered off with suction, and the solvent was spun dry. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 5.05 g of a white solid compound, yield 59％,mp:69.5-71.0℃. MS(ESI)m/z:256[M+H]+.1H NMR(400MHz,DMSO-d6)δ:7.43-7.42(m,2H),7.39-7.36(m,2H), 7.32-7.30(m,1H),6.94-6.92(m,2H),6.90-6.88(m,2H),5.03(s,2H),4.23(dd,J＝1.6,7.6Hz,1H),3.76(q,J＝4.4Hz,1H),3.30-3.27(m,1H),2.82-2.81(m,1H),2.68-2.67(m,1H).
Example 38
N- (3- (4-benzyloxy-phenoxy) -2-hydroxypropyl) cyclopentylamine (O2)
Epoxide 5 (450 mg,1.6 mmol) and cyclopentylamine (0.25 mL,2.5 mmol) were dissolved in 15mL DMF. Heated to 100 ℃ and stirred for 60 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (25 mL. Times.3). The organic phases were combined, dried over anhydrous Na 2SO4 and concentrated to give the crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give O2 as a white solid in yield 10％, mp:151.6-154.9℃.1H NMR(500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H), 7.31(t,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),3.89-3.86(m,2H),3.84-3.81(m,1H),3.12-3.10(m,1H),2.77-2.74(m,1H),2.65-2.61(m,1H),1.79-1.74(m,2H),1.62-1.59 (m,2H),1.51-1.42(m,2H),1.39-1.34(m,2H).13C NMR(105MHz,DMSO-d6)δ:152.8,152.4,137.4, 128.4,127.7,127.6,115.7,115.4,71.0,69.6,67.5,59.1,50.6,31.7,23.6.HRMS(ESI):calcd for C21H28O3N [M+H]+,342.2064,found 342.2059.
Example 39
4- (2- (2- (Cyclohexylamino) ethoxy) phenol (4 b)
Using compound C3 as raw material, obtaining white oily matter 4b according to the preparation method of compound 4a, yield 92％,mp:106.4-107.4℃. MS(ESI)m/z:280[M+H]+.1H NMR(500MHz,DMSO-d6)δ:8.89(s,1H),6.74(d,J＝8.5Hz,2H),6.65 (d,J＝8.5Hz,2H),3.96(t,J＝4.5Hz,2H),3.65(t,J＝4.5Hz,2H),3.48(t,J＝5.5Hz,2H),2.67(t,J＝5.5Hz,2H),2.35-2.31(m,1H),1.78-1.76(m,2H),1.65-1.63(m,2H),1.55-1.52(m,1H),1.22-1.09(m,3H), 0.97-0.93(m,2H).
Example 40
N- (2- (2- (4- (2-nitrobenzyloxy) phenoxy) ethoxy) ethyl) cyclohexylamine (S1)
The white oily matter S1 is obtained by taking the compound 4-nitrobenzyl bromide and 4B as raw materials according to the preparation method of the compound B1, and the yield is 75％.1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.82(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.61(t,J ＝7.5Hz,1H),7.46(t,J＝7.5Hz,1H),6.69(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.92(s,2H),3.87(t,J＝4.5Hz,2H),3.51(t,J＝4.5Hz,2H),3.27(t,J＝6.5Hz,2H),2.59(t,J＝6.5Hz,2H),2.36-2.32(m, 1H),1.70-1.68(m,4H),1.53-1.51(m,1H),1.17-1.03(m,5H).13C NMR(105MHz,DMSO-d6)δ:151.2, 151.1,149.4,135.7,132.5,130.9,128.0,123.8,115.6,115.3,70.1,68.9,67.5,60.8,52.1,49.6,28.4,25.7,25.6.
Example 41
N- (2- (2- (4- (2-chlorobenzyloxy) phenoxy) ethoxy) ethyl) cyclohexylamine (S2)
The white solid S2 is obtained by taking the compound 4-chlorobenzyl bromide and 4B as raw materials according to the preparation method of the compound B1, and the yield is 60％,mp: 100.1-102.3℃..1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.34(d,J＝8.5Hz,2H),7.31(d,J＝8.5 Hz,2H),6.70(d,J＝8.5Hz,2H),6.65(d,J＝8.5Hz,2H),3.90(t,J＝4.5Hz,2H),3.62(s,2H),3.58(t,J＝ 4.5Hz,2H),3.38(t,J＝6.5Hz,2H),2.62(t,J＝6.5Hz,2H),2.42-2.38(m,1H),1.74-1.69(m,4H),1.54-1.52(m,1H),1.21-1.01(m,5H).13C NMR(105MHz,DMSO-d6)δ:151.3,151.2,140.7,130.8,129.8, 127.9,115.6,115.3,70.3,68.9,67.5,59.8,53.7,49.6,28.5,25.8,25.7.
Example 42
Methyl 4- ((4- (2- (2-cyclohexylamino) ethoxy) phenoxy) methyl) benzoate (S3)
The white oily matter S3 is obtained by taking the compound 4-bromomethyl benzoate and 4B as raw materials according to the preparation method of the compound B1, and the yield is 23％.1H NMR(500MHz,DMSO-d6)δ:8.88(s,1H),7.87(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H), 6.69(d,J＝9.0Hz,2H),6.64(d,J＝9.0Hz,2H),3.89(t,J＝4.5Hz,2H),3.83(s,3H),3.72(s,2H),3.57(t,J＝4.5Hz,2H),3.39(t,J＝6.5Hz,2H),2.64(t,J＝6.5Hz,2H),2.44-2.39(m,1H),1.76-1.69(m,4H), 1.54-1.52(m,1H),1.24-1.02(m,5H).13C NMR(105MHz,DMSO-d6)δ:166.2,151.3,151.2,147.8,129.0, 128.2,127.8,115.6,115.3,70.3,68.9,67.5,60.1,54.3,52.0,49.9,28.6,25.8,25.6.
Example 43
N- (2- (2- (4- ((4- (benzyloxy) benzyl) oxy) phenoxy) ethoxy) ethyl) cyclohexylamine (S4)
The compound 4-benzyloxy bromobenzyl and 4B are taken as raw materials, and light yellow oily matter S4 is obtained according to the preparation method of the compound B1, and the yield is 65％.1H NMR(400MHz,DMSO-d6)δ:8.89(s,1H),7.43(d,J＝6.8Hz,2H),7.38(t,J＝7.2Hz,2H),7.32(t,J ＝7.2Hz,1H),7.21(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),6.73-6.70(m,2H),6.66-6.64(m,2H),5.05(s,2H),3.91-3.89(m,2H),3.59-3.57(m,2H),3.55(s,2H),3.36(t,J＝6.4Hz,2H),2.59(t,J＝6.4Hz, 2H),2.44-2.38(m,1H),1.74-1.69(m,4H),1.55-1.52(m,1H),1.25-1.01(m,5H).13C NMR(105MHz, DMSO-d6)δ:157.0,151.3,151.2,137.2,133.3,129.2,128.4,127.7,127.6,115.7,115.3,114.3,70.4,69.1, 68.9,67.5,59.4,53.9,49.2,28.5,25.9,25.7.
Example 44
1- (Benzyloxy) -4- (2- (2- (cyclohexyloxy) ethoxy) benzene (S5)
The compound cyclohexanol is used as a raw material, and light yellow oily matter S5 is obtained according to the preparation method of the compound XST20, and the yield is high 19％.1H NMR (500MHz,DMSO-d6)δ:7.42(d,J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d, J＝9.0Hz,2H),6.86(d,J＝9.0Hz,2H),5.03(s,2H),4.00(t,J＝4.5Hz,2H),3.70(t,J＝4.5Hz,2H),3.55-3.51(m,4H),3.24-3.22(m,1H),1.81-1.80(m,2H),1.65-1.63(m,2H),1.47-1.46(m,1H),1.22-1.15 (m,5H).13C NMR(105MHz,DMSO-d6)δ:152.6,152.4,137.4,128.4,127.7,127.6,115.7,115.3,76.7, 70.3,69.6,69.1,67.5,66.6,31.8,25.4,23.5.
Example 45
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -2-furanamine (CC 1)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 70％.1H NMR(400MHz,DMSO-d6)δ:7.88 (d,J＝7.2Hz,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.00(d,J＝ 7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.83(d,J＝9.2Hz,2H),6.68(t,J＝7.2Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
Example 46
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -2-thiazolamine (CC 2)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 57％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.22(d,J＝7.2Hz,1H),6.88(d,J＝ 9.2Hz,2H),6.83(d,J＝9.2Hz,2H),6.75(d,J＝7.2Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
Example 47
6- ((2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethyl) amino) -1, 3-dimethyluracil (CC 3)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 35％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.83(d,J＝ 9.2Hz,2H),5.16(s,2H),4.50(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz,2H),3.16(s,3H),3.01(s,3H),2.73(t,J＝5.6Hz,2H).
Example 48
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -4-chloroaniline (CC 4)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 75％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.27(d,J＝7.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),6.84(d,J＝9.2Hz,2H),6.54(d,J＝7.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
Example 49
N-2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl-2-pyridinamine (CC 5)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 52％.1H NMR(400MHz,DMSO-d6)δ:8.07 (d,J＝7.0Hz,1H),7.86(t,J＝7.0Hz,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝ 7.2Hz,1H),7.13(d,J＝7.0Hz,1H),6.88(d,J＝9.2Hz,2H),6.84(d,J＝9.2Hz,2H),6.62(t,J＝7.0Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6 Hz,2H).
Example 50
2- (2- (4- (Benzyloxy) phenoxy) ethoxy) -N-methylethylamine (CC 6)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 63％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.83(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝5.6Hz,2H),3.26(s,3H),2.72(t,J＝5.6Hz,2H).
Example 51
2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethylamine (CC 7)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 47％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.82(d,J＝ 9.2Hz,2H),5.16(s,2H),5.11(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz,2H),3.07(t,J＝5.6Hz,2H).
Example 52
2- (2- (2- (4- (Benzyloxy) phenoxy) ethoxy) amino) acetic acid (CC 8)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 48％.1H NMR(400MHz,DMSO-d6)δ:10.8 (s,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H), 6.82(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝5.6Hz,2H),3.49(s,2H),2.72(t,J＝5.6Hz,2H).
Example 53
2- (2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethyl) aminotetrahydrofuran (CC 10)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 51％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),5.16(s,2H),4.88(t,J＝4.4Hz,1H),4.31(t,J＝4.8Hz,2H),3.78(t,J＝4.8Hz,2H),3.49(t,J＝5.6Hz,2H),3.80-3.70(m,2H),2.72(t,J＝5.6Hz,2H),2.05-1.90(m,2H),1.90-1.80(m,2H).
Example 54
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) aminomorpholine (CC 11)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 60％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.84(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz,2H),3.68-3.60(m,4H),3.11-2.87(m,4H),2.82(t,J＝5.6Hz,2H).
Example 55
1-Methyl-4- (2- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) amino) piperazine (CC 12)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 51％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.84(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.76(t,J＝5.6Hz,2H),2.82(t,J＝5.6Hz,2H),2.95-2.60(m,4H),2.40-2.30(m,4H),2.26(s,3H).
Example 56
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) tetrahydro-2H-pyran-2-amine (CC 14)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 63％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.73(t,J＝4.4Hz,1H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.49(t,J＝5.6Hz,2H),3.65-3.55(m,2H),2.72(t,J＝5.6Hz,2H),1.90-1.65(m,2H),1.65-1.55(m,4H).
Example 57
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) piperidin-2-amine (CC 15)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 47％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.87(t,J＝4.4Hz,1H),3.79(t,J＝4.8Hz,2H),3.49(t,J＝5.6Hz,2H),2.72(t,J＝5.6Hz,2H),2.71-2.69(m,2H),1.71-1.60(m,2H),1.55-1.40(m,4H).
Example 58
(2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethyl) carbamic acid (CC 16)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 64％.1H NMR(400MHz,DMSO-d6)δ:10.8 (s,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz, 2H),3.04(t,J＝5.6Hz,2H).
Example 59
(2- (2- (4- (Benzyloxy) phenoxy) ethoxy) ethyl) carbamic acid methyl ester (CC 17)
According to the preparation method of the compound XST20, light yellow liquid is obtained, and the yield is high 27％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz,2H),3.04(t,J＝5.6Hz,2H),3.68(s,1H).
Example 60
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) propanamide (CC 18)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 66％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz,2H),3.28(t,J＝5.6Hz,2H),2.27(m,2H),1.02(m,3H).
Example 61
Methyl 2- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) aminoacetate (CC 19)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 40％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.68(s,3H),3.62(t,J＝5.6Hz,2H),3.51(m,2H),2.72(t,J＝5.6Hz,2H).
Example 62
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -1H-pyrrol-2-amine (CC 21)
According to the preparation method of the compound XST20, white solid is obtained, and the yield is high 75％.1H NMR(400MHz,DMSO-d6)δ:7.47(d, J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.95(d,J＝7.0Hz,1H),6.88(d,J＝9.2 Hz,2H),6.84(d,J＝9.2Hz,2H),6.40(d,J＝7.0Hz,1H),6.15(t,J＝7.0Hz,1H),5.16(s,2H),5.00(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
Example 63
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) thiophen-2-amine (CC 22)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 64％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.87(d,J＝9.2Hz,2H),6.84(d,J＝7.0Hz,1H),6.72(t,J＝7.0Hz,1H),6.01(d,J＝7.0Hz,1H),5.16(s,2H),4.31(t, J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
Example 64
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) pyrimidin-4-amine (CC 23)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 52％.1H NMR(400MHz,DMSO-d6)δ:8.43 (s,1H),8.40(d,J＝7.0Hz,1H),7.47(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.87(d,J＝9.2Hz,2H),6.44(d,J＝7.0Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz, 2H),3.79(t,J＝4.4Hz,2H),3.73(t,J＝5.6Hz,2H),3.46(t,J＝5.6Hz,2H).
Example 65
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -4-methoxyaniline (CC 24)
According to the preparation method of the compound XST20, white solid is obtained, and the yield is high 66％.1H NMR(500MHz,DMSO-d6)δ:7.47(d, J＝7.0Hz,2H),7.38(t,J＝7.0Hz,2H),7.31(t,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),6.86(d,J＝9.0 Hz,2H),6.77(d,J＝9.0Hz,2H),6.70(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.5Hz,2H),3.83(s,3H),3.79(t,J＝4.5Hz,2H),3.73(t,J＝6.0Hz,2H),3.46(t,J＝6.0Hz,2H).
Example 66
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -1-methyl-1, 4,5, 6-tetrahydropyridin-2-amine (CC 25)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 59％.1H NMR(400MHz,DMSO-d6)δ:7.47 (d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝ 9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.76(t,J＝5.6Hz,2H),3.23(t,J＝4.4Hz,1H),3.04(s,3H),2.73(t,J＝5.6Hz,2H),2.55-1.96(m,4H),1.71-1.45(m,2H).
Example 67
N- (2- (2- (4- (benzyloxy) phenoxy) ethoxy) ethyl) -2-pyrrolidinamine (CC 26)
According to the preparation method of the compound XST20, white solid is obtained, and the yield is high 59％.1H NMR(400MHz,DMSO-d6)δ:7.47(d, J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,2H),6.88(d,J＝9.2 Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.90-3.80(m,1H),3.79(t,J＝4.8Hz,2H),3.49(t,J＝5.6Hz,2H),3.23(t,J＝4.4Hz,1H),3.04(s,3H),2.90-2.75(m,2H),2.72(t,J＝5.6Hz,2H),1.79-1.54(m, 4H).
Example 68
N- (2- (2- (4- (3-methoxybenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 2)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 47％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.27(t,J＝8.4Hz,1H),7.14(s,1H),7.03(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),4.31(t,J＝4.4Hz,2H),3.83(s,3H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝ 4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 69
N- (2- (2- (4- (3, 4-dimethoxybenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 3)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 41％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.03(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.81(d,J＝8.0Hz,1H),6.55(d,J＝8.0Hz,1H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s, 2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 70
N- (2- (2- (4- (2, 6-dimethoxybenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 4)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 30％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.16(t,J＝8.0Hz,,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.48(d,J＝8.0Hz,2H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),2.72(t, J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 71
N- (2- (2- (4- (2-methoxybenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 5)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 32％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.25(d,J＝8.4Hz,1H),6.94(t,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),4.31(t,J＝4.4Hz,2H),3.83(s,3H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz, 2H),3.54(s,2H),3.10-3.00(m,1H),2.72(t,J＝4.8Hz,2H),1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
Example 72
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) -2-methoxyphenol (BD 6)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 45％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.97(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.77(d,J＝8.0Hz,1H),6.49(d,J＝8.0Hz,1H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 73
N- (2- (2- (4- (3, 4, 5-trimethoxybenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 7)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 35％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.59(s,2H),4.31(t,J＝4.4Hz,2H),3.83(s,9H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H), 1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 74
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) -1, 2-benzenediol (BD 8)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 51％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.93(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.71(d,J＝8.0Hz,1H),6.49(d,J＝8.0Hz,1H),5.35(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H),3.54(s, 2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 75
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) phenol (BD 9)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 40％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),6.93(d,J＝9.2Hz,2H),6.88(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),6.68(d,J＝9.2Hz,2H), 5.35(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.8Hz,2H),3.62(t,J＝6.4Hz,2H),3.54(s,2H),3.10-3.00(m,1H),2.72(t,J＝6.4Hz,2H),1.71-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
Example 76
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) -N-methylaniline (BD 12)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 60％.1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.14(d,J＝8.8Hz,2H),6.93(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),6.53(d,J＝8.8Hz,2H), 4.31(t,J＝6.4Hz,2H),4.00(s,1H),3.91(s,2H),3.79(t,J＝6.4Hz,2H),3.62(t,J＝6.4Hz,2H),3.10-3.00(m,1H),2.72(t,J＝6.4Hz,2H),2.68(s,3H),1.72-1.68(m,2H),1.60-1.50(m,2H),1.45-1.35(m, 4H).
Example 77
3- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) phenol (BD 13)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 43％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.21(t,J＝7.0Hz,1H),7.10(s,1H),7.03(d,J＝7.0Hz,2H),6.92(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),6.88(d,J＝7.0Hz,2H),5.35(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝ 4.8Hz,2H),3.54(s,2H),2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 78
2- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) phenol (BD 14)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 47％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.21(t,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,1H),6.94(t,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),5.34(s,1H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz, 2H),3.62(t,J＝4.8Hz,2H),3.54(s,2H),3.10-3.00(m,1H),2.72(t,J＝4.8Hz,2H),1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
Example 79
N- (2- (2- (4- (2-methylbenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 17)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 55％.1H NMR(500MHz,DMSO-d6)δ:8.91(s, 1H),7.39(d,J＝7.0Hz,1H),7.26(t,J＝7.0Hz,1H),7.24(d,J＝7.0Hz,1H),7.19(t,J＝7.0Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),5.28(s,2H),4.31(t,J＝4.5Hz,2H),3.79(t,J＝4.5Hz,2H), 3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),2.34(s,3H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 80
N- (2- (2- (4- (3-methylbenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 18)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 62％.1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.48(t,J＝7.6Hz,1H),7.28(d,J＝7.6Hz,1H),7.23(s,1H),7.16(d,J＝7.6Hz,1H),6.90(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),4.93(s,2H),4.31(t,J＝7.0Hz,2H),3.79-3.60(m,4H),3.10-3.05(m, 1H),2.72(t,J＝7.0Hz,2H),2.34(s,3H),1.78-1.68(m,2H),1.60-1.55(m,2H),1.45-1.37(m,4H).
Example 81
N- (2- (2- (4- (2, 4-dimethoxybenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 19)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 50％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.14(d,J＝8.0Hz,1H),6.62(s,1H),6.90(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.48(d,J＝8.0Hz,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.83(s,6H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝4.8Hz,2H), 2.72(t,J＝6.4Hz,2H),2.64-2.60(m,1H),1.72-1.56(m,4H),1.57-1.46(m,4H).
Example 82
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) -N, N-dimethylaniline (BD 20)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 52％.1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.18(d,J＝8.8Hz,2H),6.93(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),6.69(d,J＝8.8Hz,2H),4.31(t,J＝6.4Hz,2H),3.91(s,2H),3.79(t,J＝6.4Hz,2H),3.62(t,J＝6.4Hz,2H),3.06(s,6H), 3.05-3.00(m,1H),2.72(t,J＝6.4Hz,2H),1.72-1.68(m,2H),1.60-1.50(m,2H),1.45-1.35(m,4H).
Example 83
2- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) -N-methylaniline (BD 21)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 47％.1H NMR(500MHz,DMSO-d6)δ:8.91(s, 1H),7.16(t,J＝7.0Hz,1H),7.14(d,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H), 6.70(t,J＝7.0Hz,1H),6.68(d,J＝7.0Hz,1H),5.16(s,2H),4.31(t,J＝4.5Hz,2H),3.79(t,J＝4.5Hz,2H),3.62(t,J＝6.0Hz,2H),3.09(s,3H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H), 1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 84
3- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) -N-methylaniline (BD 22)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 63％.1H NMR(400MHz,DMSO-d6)δ:8.88(s, 1H),7.16(t,J＝7.6Hz,1H),6.90(d,J＝7.6Hz,2H),6.88(d,J＝7.6Hz,2H),6.79(d,J＝7.6Hz,1H),6.76(d,J＝7.6Hz,1H),6.65(s,1H),5.16(s,2H),4.31(t,J＝7.0Hz,2H),3.79-3.60(m,4H),3.10-3.05(m, 1H),2.72(t,J＝7.0Hz,2H),2.68(s,3H),1.78-1.68(m,2H),1.60-1.55(m,2H),1.45-1.37(m,4H).
Example 85
N- (2- (2- (4- (3-chlorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 23)
According to the preparation method of the compound B1, white solid is obtained in yield 53％.1H NMR(400MHz,DMSO-d6)δ:8.91(s,1H), 7.56(s,1H),7.42(d,J＝7.2Hz,1H),7.35(d,J＝7.2Hz,1H),7.32(t,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0 Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 86
N- (2- (2- (4- (2, 4-dichlorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 25)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 41％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.73(s,1H),7.30(d,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H), 3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 87
N- (2- (2- (4- (3, 4-dichlorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 26)
According to the preparation method of the compound B1, light yellow solid is obtained, and the yield is high 40％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.50(s,1H),7.66(d,J＝7.2Hz,1H),7.18(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝ 9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 88
N- (2- (2- (4- (2, 5-dichlorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 27)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 61％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.50(s,1H),7.66(d,J＝7.2Hz,1H),7.36(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H), 3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 89
N- (2- (2- (4- (4-fluorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 28)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 51％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.34(d,J＝7.2Hz,2H),7.17(d,J＝7.2Hz,2H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H), 5.16(s,2H),3.91(t,J＝4.8Hz,2H),3.58(t,J＝4.8Hz,2H),3.44(t,J＝6.4Hz,2H),3.11-3.05(m,1H),2.60(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
Example 90
N- (2- (2- (4- (2, 4-difluorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 29)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 50％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.32(d,J＝7.2Hz,1H),6.94(d,J＝7.2Hz,1H),6.90(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H), 6.61(s,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 91
N- (2- (2- (4- (2, 5-difluorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 30)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 57％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.15(d,J＝7.2Hz,2H),6.93(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),6.80(s,1H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0 Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 92
N- (2- (2- (4- (3-fluorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 31)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 63％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.36(t,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),7.17(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H), 6.90(s,1H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H), 1.47-1.37(m,4H).
Example 93
3- ((Ethyl 4- (2- (2- (cyclopentylamino) ethoxy) phenoxy) methyl) benzoate (BD 32)
According to the preparation method of the compound B7, off-white solid is obtained, and the yield is increased 51％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.98(d,J＝7.2Hz,1H),7.89(s,1H),7.68(d,J＝7.2Hz,1H),7.35(t,J＝7.2Hz,1H),6.93(d,J＝9.0 Hz,2H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04(m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m, 4H).
Example 94
3- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzamide (BD 34)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 56％.1H NMR(400MHz,CD3OD)δ:7.96(d,J ＝7.6Hz,1H),7.87(s,1H),7.72(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),6.76(d,J＝9.2Hz,2H),6.68 (d,J＝9.2Hz,2H),5.16(s,2H),4.33-4.30(m,2H),3.89-3.86(m,1H),3.83-3.79(m,4H),3.37-3.34(m,2H),2.20-2.15(m,2H),1.89-1.79(m,4H),1.71-1.60(m,2H).
Example 95
N- (2- (2- (4- (4-bromobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 35)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 60％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.90(d,J＝7.2Hz,2H),7.25(d,J＝7.2Hz,2H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.62(t,J＝6.4Hz,2H),3.11-3.05(m,1H), 2.72(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
Example 96
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzonitrile (BD 36)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 52％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.57(d,J＝7.2Hz,2H),7.54(d,J＝7.2Hz,2H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),3.62(t,J＝6.4Hz,2H),3.11-3.05(m,1H), 2.72(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
Example 97
N- (2- (2- (4- (2-chlorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 37)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 59％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.70(d,J＝7.2Hz,1H),7.32(t,J＝7.2Hz,1H),7.30(d,J＝7.2Hz,1H),7.26(t,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz, 2H),3.58(t,J＝6.4Hz,2H),3.11-3.05(m,1H),2.60(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
Example 98
N- (2- (2- (4- (2-fluorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 38)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 53％.1H NMR(400MHz,DMSO-d6)δ:8.89(s, 1H),7.68(t,J＝7.2Hz,1H),7.53(d,J＝7.2Hz,1H),7.34(d,J＝7.2Hz,1H),7.15(d,J＝7.2Hz,1H),6.88(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),5.16(s,2H),4.31(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz, 2H),3.58(t,J＝6.4Hz,2H),3.11-3.05(m,1H),2.60(t,J＝6.4Hz,2H),1.71-1.68(m,2H),1.57-1.55(m,2H),1.43-1.34(m,4H).
Example 99
N- (2- (2- (4- (3, 4-difluorobenzyloxy) phenoxy) ethoxy) ethyl) cyclopentylamine (BD 39)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 37％.1H NMR(400MHz,DMSO-d6)δ:8.91(s, 1H),7.15(d,J＝7.2Hz,1H),7.11(d,J＝7.2Hz,1H),6.93(d,J＝9.0Hz,2H),6.90(s,1H),6.88(d,J＝9.0Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H),3.62(t,J＝6.0Hz,2H),3.07-3.04 (m,1H),2.72(t,J＝6.0Hz,2H),1.74-1.64(m,2H),1.60-1.52(m,2H),1.47-1.37(m,4H).
Example 100
4- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzamide (BD 41)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 48％.1H NMR(400MHz,CD3OD)δ:7.96(d,J ＝8.0Hz,2H),7.54(d,J＝8.0Hz,2H),6.79(d,J＝4.8Hz,2H),6.71(d,J＝4.8Hz,2H),5.16(s,2H),4.31 (t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H),3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).
Example 101
2- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzamide (BD 43)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 53％.1H NMR(400MHz,CD3OD)δ:7.96(d,J ＝8.0Hz,1H),7.63(t,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),6.88(d,J＝4.8Hz, 2H),6.81(d,J＝4.8Hz,2H),5.16(s,2H),4.31(t,J＝4.4Hz,2H),3.92-3.87(m,1H),3.84-3.82(m,4H),3.39(t,J＝4.4Hz,2H),2.20-2.18(m,2H),1.93-1.85(m,4H),1.69-1.66(m,2H).
Example 102
3- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzaldehyde (BD 46)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 36％.1H NMR(400MHz,CD3OD)δ:9.88(s,1H), 7.82(d,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H),7.73(s,1H),7.43(t,J＝7.6Hz,1H),6.88(d,J＝9.2Hz,2H),6.82(d,J＝9.2Hz,2H),5.16(s,2H),4.33-4.30(m,2H),3.89-3.86(m,1H),3.83-3.79(m,4H), 3.37-3.34(m,2H),2.20-2.15(m,2H),1.89-1.79(m,4H),1.71-1.60(m,2H).
Example 103
2- ((4- (2- (2- (Cyclopentylamino) ethoxy) phenoxy) methyl) benzaldehyde (BD 47)
According to the preparation method of the compound B1, off-white solid is obtained, and the yield is increased 43％.1H NMR(500MHz,CD3OD)δ:10.36(s, 1H),8.91(s,1H),7.82(d,J＝7.5Hz,1H),7.66(t,J＝7.5Hz,1H),7.57(t,J＝7.5Hz,1H),7.55(d,J＝7.5Hz,1H),6.88(d,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,2H),5.16(s,2H),4.35-4.30(m,4H),3.53(t,J＝4.5 Hz,2H),3.08-3.02(m,1H),2.57(t,J＝6.5Hz,2H),1.68-1.65(m,2H),1.58-1.52(m,2H),1.43-1.39(m,2H),1.36-1.29(m,2H).
Example 104
O- (2- (4- (benzyloxy) phenoxy) ethyl) -N-cyclopentylhydroxylamine (BD 53)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 57％.1H NMR(400MHz,DMSO-d6)δ:8.89 (s,1H),7.47(d,J＝8.0Hz,2H),7.38(t,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,2H), 6.88(d,J＝8.4Hz,2H),5.16(s,2H),4.33(t,J＝4.4Hz,2H),3.95(t,J＝4.4Hz,2H),2.67-2.62(m,1H),1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
Example 105
N- (2- (4- (benzyloxy) phenoxy) ethyl) cyclopentylamine (BD 55)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 62％.1H NMR(400MHz,DMSO-d6)δ:8.89 (s,1H),7.47(d,J＝8.0Hz,2H),7.38(t,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),5.16(s,2H),4.13(t,J＝4.4Hz,2H),2.97(t,J＝4.4Hz,2H),2.67-2.62(m,1H), 1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
Example 106
N- ((2- (4- (benzyloxy) phenoxy) ethoxy) methyl) cyclopentylamine (BD 56)
White solid is obtained according to the preparation method of the compound XST20, and the yield is 42％.1H NMR(400MHz,DMSO-d6)δ:8.89 (s,1H),7.47(d,J＝8.0Hz,2H),7.38(t,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),5.16(s,2H),4.63(s,2H),4.31(t,J＝4.4Hz,2H),3.79(t,J＝4.4Hz,2H), 2.67-2.62(m,1H),1.72-1.70(m,2H),1.60-1.50(m,2H),1.49-1.40(m,4H).
Experimental example 1 in vitro antitumor Activity assay.
The cell lines are human ovarian cancer cells SKOV3, human colon cancer cells HCT116 and human liver cancer cells HepG2, IC 50 values for inhibiting tumor proliferation of the compounds are detected, experiments are carried out by adopting a CCK8 method, cisplatin is used as a positive reference medicine, the result is the average value of 3 tests, and the IC50 values are expressed as the average value +/-SD. The results are shown in Table 1.
In vitro inhibition of three strains of tumor cells by the compounds of Table 1 50
Affinity assay of Compounds of Experimental example 2 with foxM1
By utilizing the Surface Plasmon Resonance (SPR) technology, a method for determining the affinity of small molecules and FOXM1 is established. Truncated FOXM1b protein was designed to be expressed, with an amino acid sequence of 222-360, the portion comprising the DNA binding domain of FOXM1, with His tag, and with FD16 as a positive control, the affinity of a portion of the compounds for FOXM1 was examined, and the dissociation constants (KD) were calculated according to the BIAevaluation software, and the results are shown in table 2.
Affinity K D (μM) of the Table 2 compound for FOXM1
Experimental example 3 in vivo Activity Studies
3.1 Dissolution prescription of Compound S2
In the experiment, the compound S2 is observed to be relatively high in fat solubility, and the compound dissolution prescription is first searched for in-vivo activity study. The dose of acute toxicity in vivo is set to 500mg/kg, the administration volume of each mouse is 100 mu L-200 mu L, the solubility of the compound reaches 50-100 mg/kg after preliminary calculation, and the dissolution prescription of the compound in vivo activity experiment is finally determined to be 5% DMSO+5% EtOH+20% HS15+70% H 2 O through experiments, and the solubility in the prescription can reach 51.1mg/mL.
3.2 Preliminary acute toxicity assay for Compound S2
The toxicity of compound S2 to BALB/c mice was examined primarily by intraperitoneal injection, with doses of 500mg/kg and 750mg/kg, respectively, and with doses of 0.2mL and 0.3mL, respectively, for 3 mice per group. After one-time administration, observation was made for 7 days. Mice in the 500mg/kg dose group have no death and no abnormality in activity; mice in the 750mg/kg dose group all died. The primary acute toxicity result indicates that the toxicity of the compound S2 is low, and LD 50 is more than 500mg/kg and far lower than the acute toxicity of cisplatin reported in the literature (LD 50 =12.6 mg/kg).
3.3 In vivo anti-tumor Activity study of Compound S2
The in vitro inhibition activity level of the compound S2 on SKOV3 cells and HCT116 cells is equivalent, and the activity research is carried out by adopting ovarian cancer SKOV3 cell lines. Cisplatin, the first-line clinical drug for ovarian cancer treatment, was used as a positive control, and solvent was used as a blank control.
Female BALB/c nude mice 8 weeks old were used as subjects for the study using the human SKOV3-GFP ovarian cancer model. The cells are cultured in vitro, inoculated under the right armpit of the mouse, and the tumor grows naturally for 14 days, and the volume is 90-100mm 3. The compound was dissolved in an aqueous solution containing 5%DMSO+20 Solutol HS15 and the solution was clear. Compound S2 was given in two dose groups of 25 mg/kg/day and 50 mg/kg/day, administered by intraperitoneal injection, 1 time/day for 21 days; cisplatin as a positive control drug was administered by intraperitoneal injection 3 times per week for 1 day and 21 days in a3 mg/kg/week dose group. Animals were observed daily for status, weighed twice weekly, and mouse tumor area and volume were recorded. 21 days after administration, the tumor weights were obtained and recorded. The body weight changes of the mice are shown in Table 3 and FIG. 1.
TABLE 3 weight changes in mice before and after administration
Grouping Weight/g before administration Weight/g before administration Weight gain rate
Blank solvent set 16.7±0.8 16.2±1.7 -3.0％
S2(25mg/kg) 17.4±1.0 16.7±1.2 -3.7％
S2(50mg/kg) 17.1±1.3 15.5±1.9 -9.5％
Cisplatin (cisplatin) 16.9±0.9 13.7±2.7 -20.0％
As shown in fig. 1 and table 3, the body weight of each group of mice as a whole tended to decrease to a different extent. At the end of the experiment, the average body weight of mice in the blank solvent group was reduced by 3%; cisplatin group mice died 1, mice became worse 7 days after dosing, and the average body weight was reduced by 20% at the end; s2 (50 mg/kg) mice had an average weight loss of 9.5%; the average body weight of S2 (25 mg/kg) mice was reduced by 3.7%. From this, it was found that cisplatin was somewhat toxic to mice, while compound S2 was less toxic to mice.
The tumor volume change of the mice is shown in fig. 2, the tumor volume of the mice in the blank solvent group is obviously increased, and the increasing trend of the tumor volume of each other group is slowed down compared with the ratio of the blank solvent group. The tumor volume of the compound S2 is equivalent at the high and low doses; compound S2 was able to inhibit tumor volume growth compared to the blank solvent group. At the end of the experiment, mice in the compound S2 group had greater tumor volumes than cisplatin group, but there was no significant difference (P > 0.05) between S2 (50 mg/kg) and cisplatin groups.
Tumor burden of experimental mice is observed noninvasively through FluorVivo imaging system, fluorescence imaging is carried out, tumor areas of each group of mice are recorded according to image results, and average value is calculated. As shown in fig. 3, tumor fluorescence imaging area was reduced for each of the dosing groups compared to the blank solvent group. The tumor area of the compound S2 is equivalent at the high and low doses; compared with a blank solvent group, the S2 high-low dose group has a significant difference (P < 0.01) in tumor fluorescence area, which suggests that the compound S2 has an inhibitory effect on a human ovarian cancer model under the high and low doses.
After the end of the administration, all tumors were dissected, weighed, recorded and the average calculated, and the results are shown in fig. 4. The S2 (50 mg/kg) and S2 (25 mg/kg) groups showed a significant difference in tumor weight (P < 0.01) compared to the blank solvent group, suggesting that compound S2 had an inhibitory effect on the human ovarian cancer model at both the high and low doses, and that the S2 (50 mg/kg) group had slightly less tumor weight than the low dose group. The tumor weight of compound S2 group was slightly greater than positive drug compared to cisplatin group. The tumor inhibition rate was calculated by the formula IR (%) = (average tumor weight of 1-administration group/average tumor weight of blank solvent group) ×100%, and the results are shown in table 4. The tumor inhibition rates of the S2 (25 mg/kg) group, the S2 (50 mg/kg) group and the cisplatin group were 35.2%, 37.6% and 51.8%, respectively. In the experiment, cisplatin has a strong inhibition effect on a human ovarian cancer mouse model; the high-low dose group of the compound S2 has obvious inhibition effect, but is weaker than positive medicament cisplatin, and does not show obvious dose-dependent inhibition effect.
TABLE 4 tumor weight and tumor inhibition ratio in mice
In conclusion, the positive drug cisplatin (3 mg/kg) has a strong inhibition effect in the experimental model of the mice, but 1 mouse of the group dies, which proves that the cisplatin has obvious toxic and side effects on the mice at the existing dosage. The S2 (25 mg/kg) group and the S2 (50 mg/kg) group show a certain tumor inhibition effect in the experimental model of the mice, and have no obvious toxic or side effect on the mice at high and low doses. Compound S2 inhibited the human ovarian cancer mouse model slightly less than the positive drug cisplatin, but exhibited less toxicity than cisplatin.
Slicing the collected mouse tumor tissues, detecting the expression level of the FOXM1 downstream target protein in the tumor tissues of a blank solvent group and a compound S2 high-dose group by adopting a Western blot method, and obviously down-regulating the expression of CD31 and CD34 related to tumor angiogenesis in the mouse tumor of the high-dose group compared with the expression level of the blank solvent group as shown in a result shown in a figure 5; promote the cell cycle related CDC25B, CENP-A, cyclinB1, cyclinF, PLK1 expression to be obviously down-regulated; survivin expression levels are also down-regulated. The results indicate that compound S2 down-regulates the level of its downstream target protein by inhibiting FOXM1 in tumor tissue.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (3)

1. A compound or pharmaceutically acceptable salt thereof selected from:
2. A pharmaceutical composition comprising any one of the compounds of claim 1, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
3. Use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting FOXM1, said compound or pharmaceutically acceptable salt thereof being selected from the structures:
。
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STN REGISTRY;ACS;《STN REGISTRY》;第1-3页 *
Synthesis and antineoplastic activity of ethylene glycol phenyl aminoethyl ether derivatives as FOXM1 inhibitors;Yan Gao等;《European Journal of Medicinal Chemistry》;第244卷;第114877/1-13页 *

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